Clinical Trials /

A Phase 1 Clinical Study of AZD4635 in Patients With Advanced Solid Malignancies

NCT02740985

Description:

This is a Phase 1, open-label, multicenter study of continuous oral dosing of AZD4635 administered to patients with advanced solid malignancies. Dosing will be escalated until a maximum-tolerated dose (MTD) is determined in patients. The MTD will be defined by dose-limiting toxicity. The study design allows an escalation of dose with intensive safety monitoring to ensure the safety of the patients. Expansion cohorts will further assess safety and preliminary anti-tumor activity in a variety of advanced solid tumor malignancies. Other dosing schedules and/or combinations may be evaluated based on the emerging PK and safety data. The primary objectives of this study are to: - Investigate the safety and tolerability of AZD4635 monotherapy when given orally (PO) to patients with advanced solid malignancies. - Investigate the safety, tolerability, and pharmacokinetics (PK) of AZD4635 monotherapy capsule formulation when given to patients with advanced solid malignancies. - Investigate the safety and tolerability of AZD4635 PO when given in combination with durvalumab, durvalumab plus oleclumab, or docetaxel to patients with advanced solid malignancies and to investigate the safety and tolerability of AZD4635 in combination with abiraterone acetate or enzalutamide in patients with mCRPC. - Define the maximum-tolerated dose (MTD) of AZD4635 in combination with durvalumab. - Define the recommended Phase 2 dose (RP2D) of AZD4635 in combination with abiraterone acetate or enzalutamide. - Determine the safety, tolerability, and immune effects of AZD4635 when administered in combination with durvalumab to patients with non-small cell lung cancer (NSCLC) who have previously received immunotherapy (Phase 1b portion). - Investigate the safety and tolerability of AZD4635 capsule formulation in combination with durvalumab and oleclumab when given to patients with mCRPC or advanced solid tumor malignancy. - Define the RP2D of AZD4635 capsule formulation in combination with durvalumab and oleclumab when given to patients with mCRPC or advanced solid tumor malignancy. - Investigate the safety and tolerability of AZD4635 capsule formulation in combination with docetaxel when given to patients with mCRPC or advanced solid tumor malignancy. - Define the RP2D of AZD4635 capsule formulation in combination with docetaxel when given to patients with mCRPC or advanced solid tumor malignancy.

Related Conditions:
  • Colorectal Carcinoma
  • Malignant Solid Tumor
  • Non-Small Cell Lung Carcinoma
  • Prostate Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: A Phase 1 Clinical Study of AZD4635 in Patients With Advanced Solid Malignancies
  • Official Title: A Phase 1, Open-Label, Multicenter Study to Assess Safety, Tolerability, Pharmacokinetics, and Preliminary Anti-Tumor Activity of Ascending Doses of AZD4635 Both as Monotherapy and in Combination in Patients With Advanced Solid Malignancies

Clinical Trial IDs

  • ORG STUDY ID: D8730C00001
  • SECONDARY ID: REFMAL 435
  • NCT ID: NCT02740985

Conditions

  • Advanced Solid Malignancies
  • Non-Small Cell Lung Cancer (NSCLC)
  • Metastatic Castrate-Resistant Prostate Carcinoma (mCRPC)
  • Colorectal Carcinoma (CRC)

Interventions

DrugSynonymsArms
AZD4635Arm A
DurvalumabMEDI4736Arm D
Abiraterone AcetateZytigaArm AA
EnzalutamideXtandiArm EA
OleclumabMEDI9447Arm CB
DocetaxelTaxotereArm CC

Purpose

This is a Phase 1, open-label, multicenter study of continuous oral dosing of AZD4635 administered to patients with advanced solid malignancies. Dosing will be escalated until a maximum-tolerated dose (MTD) is determined in patients. The MTD will be defined by dose-limiting toxicity. Other dosing schedules may be evaluated based on the emerging PK and safety data. The study design allows an escalation of dose with intensive safety monitoring to ensure the safety of the patients. The primary objectives of this study are to: - Investigate the safety and tolerability of AZD4635 monotherapy when given orally (PO) to patients with advanced solid malignancies. - Investigate the safety, tolerability, and pharmacokinetics (PK) of AZD4635 monotherapy capsule formulation when given to patients with advanced solid malignancies. - Investigate the safety and tolerability of AZD4635 PO when given in combination with durvalumab, durvalumab plus oleclumab, or docetaxel to patients with advanced solid malignancies and to investigate the safety and tolerability of AZD4635 in combination with abiraterone acetate or enzalutamide in patients with mCRPC. - Define the maximum-tolerated dose (MTD) of AZD4635 in combination with durvalumab. - Define the recommended Phase 2 dose (RP2D) of AZD4635 in combination with abiraterone acetate or enzalutamide. - Determine the safety, tolerability, and immune effects of AZD4635 when administered in combination with durvalumab to patients with non-small cell lung cancer (NSCLC) who have previously received immunotherapy (Phase 1b portion). - Investigate the safety and tolerability of AZD4635 capsule formulation in combination with durvalumab and oleclumab when given to patients with mCRPC or advanced solid tumor malignancy. - Define the RP2D of AZD4635 capsule formulation in combination with durvalumab and oleclumab when given to patients with mCRPC or advanced solid tumor malignancy. - Investigate the safety and tolerability of AZD4635 capsule formulation in combination with docetaxel when given to patients with mCRPC or advanced solid tumor malignancy. - Define the RP2D of AZD4635 capsule formulation in combination with docetaxel when given to patients with mCRPC or advanced solid tumor malignancy.

Detailed Description

      The study will be conducted in two segments. The first segment of the study, designated Phase
      1a, will be a dose escalation design in order to assess the safety, tolerability,
      pharmacokinetics (PK), and preliminary anti-tumor activity of ascending doses of AZD4635 as
      monotherapy, in combination with durvalumab or durvalumab plus oleclumab, and in combination
      with either abiraterone acetate or with enzalutamide.

      A capsule formulation of AZD4635 will be evaluated in 3 arms (arms CA, CB, and CC). An oral
      nanoparticle suspension in water constituted extemporaneously by the patient will be
      administered in all other treatment arms. Most patients who started therapy with the
      nanoparticle suspension will transition to the capsule dosage form depending the arm they are
      assigned to and emerging data. Active patients in arms F, G, H, I, J, K, KD, and L will
      continue taking the nano-suspension formulation. Patients in study arms AA and AE receiving
      AZD4635 as the nanoparticle suspension should change over to the capsule formulation as soon
      as possible at the discretion of the Investigator. Active and long-standing patients in Arms
      C, D, and E currently taking the nano-suspension formula should not be switched until further
      discussion with the Medical Monitor.

      The dose escalation arms are described as follows:

        -  Arms A, B, and C (dose escalation of AZD4635 monotherapy).

        -  Arms CA, CB, and CC. In arm CA, the safety, tolerability and PK of the capsule
           formulation will be assessed in approximately 6 patients with advanced solid
           malignancies to ensure at least 5 patients have evaluable pharmacokinetic sampling. Two
           additional arms will evaluate the safety and tolerability of the AZD4635 capsule
           formulation when combined with oleclumab plus durvalumab and in combination with
           docetaxel in patients with advanced solid malignancies. Arm CB will assess the safety
           and tolerability and determine the RP2D of the AZD4635 capsule plus durvalumab and
           oleclumab in approximately 12 patients. Arm CC will assess the safety, tolerability and
           determine the RP2D of AZD4635 capsule plus docetaxel in approximately 12 patients .

        -  Arms D and E [dose escalation of AZD4635 in combination with durvalumab anti-programmed
           death-ligand 1 (PD-L1)].

      Arms A through E enrolled 38 patients in Phase 1a in order to establish the Recommended Phase
      2 Dose (RP2D) of the nanoparticle suspension formulation of AZD4635 as a single agent or in
      combination with durvalumab.

      ● Arms EA and AA. Arms EA and AA [dose escalation of AZD4635 in combination with either
      abiraterone acetate plus prednisone or enzalutamide in patients with metastatic
      castrate-resistant prostate cancer (mRCPC)]. The AZD4635 plus hormonal therapy cohorts will
      enroll concurrently. Patients who previously received abiraterone acetate as part of their
      first-line treatment for mCRPC will be enrolled to the enzalutamide plus AZD4635 cohort (Arm
      EA). Patients who previously received enzalutamide or apalutamide as part of their first-line
      treatment for mCRPC will be enrolled to an abiraterone acetate plus AZD4635 cohort (Arm AA).

      Approximately 24 to 48 patients with mCRPC will be treated in the AZD4635 plus hormonal
      therapy arms in order to establish the RP2D.

      In Phase 1a approximately 48-86 patients will be treated with AZD4635 as a single agent or in
      combination with durvalumab, durvalumab plus oleclumab, docetaxel, abiraterone acetate or
      enzalutamide.

        -  Arm F - AZD4635 in combination with durvalumab. Post-immunotherapy non-small cell lung
           cancer (NSCLC). [15 patients]

        -  Arm G - AZD4635 monotherapy. Post-immunotherapy NSCLC. [15 patients]

        -  Arm H - AZD4635 monotherapy. Immune checkpoint resistant malignancies, previously
           treated with approved immunotherapy and progressed or responded and then stopped
           responding (e.g. renal cell carcinoma, head and neck carcinoma, or MSI high cancers
           which have approved settings for anti-PD-1 treatment).[20 patients]

        -  Arm I - AZD4635 in combination with durvalumab. Immune checkpoint naïve mCRPC.[40
           patients]

        -  Arm J - AZD4635 monotherapy. Immune checkpoint naïve CRPC. [40 patients]

        -  Arm K - AZD4635 monotherapy. Immune checkpoint naïve colorectal carcinoma (CRC). CRC,
           excluding MSI high, which has not been treated with immune checkpoint inhibitors. [20
           patients]

        -  Arm KD - AZD4635 in combination with durvalumab. Immune checkpoint naïve CRC. CRC,
           excluding MSI high, which has not been treated with immune checkpoint inhibitors. [20
           patients]

        -  Arm L - AZD4635 monotherapy. Other solid tumours immune checkpoint naïve.
           Relapsed/refractory tumors which have not been treated with immune checkpoint
           inhibitors. [20 patients]

      Patients will be randomly assigned between open-label arms with AZD4635 monotherapy and
      AZD4635 combined with durvalumab in NSCLC (Arms F/G) and mCRPC (Arms I/J) in order to
      minimize bias.

      Patients with CRC, excluding MSI high, will be enrolled to AZD4635 monotherapy (Arm K) and
      AZD4635 combined with durvalumab (Arm KD) in patients with CRC.

      Some arms will have a mandatory biopsy subgroup to ensure sufficient tissue is collected to
      assess the mechanism of action in tissue without excluding patients with nonbiopsiable
      disease. Biopsies are optional in all other arms.
    

Trial Arms

NameTypeDescriptionInterventions
Arm AExperimentalAZD4635 monotherapy as nanoparticle suspension 125 mg BID
  • AZD4635
Arm BExperimentalAZD4635 monotherapy as nanoparticle suspension 75 mg QD
  • AZD4635
Arm CExperimentalAZD4635 monotherapy as nanoparticle suspension 100 mg QD
  • AZD4635
Arm DExperimentalAZD4635 as nanoparticle suspension 75 mg QD plus durvalumab
  • AZD4635
  • Durvalumab
Arm EExperimentalAZD4635 as nanoparticle suspension 100 mg QD plus durvalumab
  • AZD4635
  • Durvalumab
Arm EAExperimentalAZD4635 as nanoparticle suspension plus enzalutamide
  • AZD4635
  • Enzalutamide
Arm AAExperimentalAZD4635 as nanoparticle suspension plus abiraterone acetate
  • AZD4635
  • Abiraterone Acetate
Arm FExperimentalAZD4635 as nanoparticle suspension plus durvaluamb in patients post immunotherapy with non-small cell lung cancer. Patients will be allocated randomly (1:1) between Arms F and G.
  • AZD4635
  • Durvalumab
Arm GExperimentalAZD4635 monotherapy as nanoparticle suspension in patients post immunotherapy with non-small cell lung cancer. Patients will be allocated randomly (1:1) between Arms F and G.
  • AZD4635
Arm HExperimentalAZD4635 monotherapy as nanoparticle suspension in patients post immunotherapy with other solid tumours.
  • AZD4635
Arm IExperimentalAZD4635 as nanoparticle suspension plus durvalumab in immunotherapy naïve patients with metastatic castration resistant prostate cancer. Patients will be allocated randomly (1:1) between Arms I and J.
  • AZD4635
  • Durvalumab
Arm JExperimentalAZD4635 as nanoparticle suspension plus durvalumab in immunotherapy naïve patients with metastatic castration resistant prostate cancer. Patients will be allocated randomly (1:1) between Arms I and J.
  • AZD4635
  • Durvalumab
Arm KExperimentalAZD4635 monotherapy as nanoparticle suspension in immunotherapy naïve patients with colorectal carcinoma.
  • AZD4635
Arm KDExperimentalAZD4635 as nanoparticle suspension plus durvalumab in immunotherapy-naïve patients with colorectal carcinoma.
  • AZD4635
  • Durvalumab
Arm LExperimentalAZD4635 monotherapy as nanoparticle suspension in immunotherapy naïve patients with other solid tumours.
  • AZD4635
Arm CAExperimentalAZD4635 capsule formulation monotherapy 75 mg QD. The pharmacokinetics of the single dose AZD4635 capsule formulation will be characterized on Cycle 1 Day 1 in Arm CA. Steady-state pharmacokinetics will be assessed on Cycle 1 Day 15. Cycle 1 and Cycle 2 will be administered in 3-week cycles to assess the safety and dose-limiting toxicity (DLT). After Cycle 1, PKs will be collected on Day 1 of every even numbered cycle (Cycles 2, 4, 6 and 8).
  • AZD4635
Arm CBExperimentalAZD4635 capsule formulation 50 mg QD plus durvalumab and oleclumab. The pharmacokinetics of the single dose AZD4635 capsule formulation will be characterized on Cycle 1 Day 1 in Arm CB. Steady-state pharmacokinetics will be assessed on Cycle 1 Day 15. Cycle 1 and Cycle 2 will be administered in 3-week cycles to assess the safety and dose-limiting toxicity (DLT). After Cycle 1, PKs will be collected on Day 1 of every even numbered cycle (Cycles 2, 4, 6 and 8).
  • AZD4635
  • Durvalumab
  • Oleclumab
Arm CCExperimentalAZD4635 capsule formulation 50 mg QD plus docetaxel. The pharmacokinetics of the single dose AZD4635 capsule formulation will be characterized on Cycle 1 Day 1 in Arm CC. Steady-state pharmacokinetics will be assessed on Cycle 1 Day 15. Cycle 1 and Cycle 2 will be administered in 3-week cycles to assess the safety and dose-limiting toxicity (DLT). After Cycle 1, PKs will be collected on Day 1 of every even numbered cycle (Cycles 2, 4, 6 and 8).
  • AZD4635
  • Docetaxel

Eligibility Criteria

        Inclusion Criteria

          1. Patient must consent to the study and provide a signed and dated, written informed
             consent document prior to any study-specific procedures, sampling, or analyses.

          2. Age ≥ 18

          3. Weight > 77 lbs. (35 kg)

          4. Availability of an archival tumor tissue sample. If archival tumour tissue is not
             available, then tissue from a fresh biopsy can be used.

          5. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 with no clinical
             deterioration over the previous 2 weeks and likely able to complete at least 9 weeks
             of treatment.

          6. Normotensive or well controlled blood pressure (systolic <140 and diastolic <90) with
             or without current anti-hypertensive treatment. If there is a diagnosis or history of
             hypertension, patient must have adequately controlled BP on a maximum of 2
             anti-hypertensive medications, as demonstrated by 2 BP measurements taken in the
             clinical setting by a medical professional within 1 week prior to enrollment. It is
             strongly recommended that patients who are on anti-hypertensive medications be
             followed by a cardiologist or a primary care physician for management of BP while on
             the study. Patients on anti-hypertensive medication must be willing and able to check
             and record twice daily BP readings for a minimum of 3 weeks.

          7. Females should be using adequate contraceptive measures from the time of screening
             until 3 months after study discontinuation, should not be breast feeding and must have
             negative pregnancy test prior to the start of dosing, or must have evidence of
             non-child-bearing potential by fulfilling one of the following criteria at screening:

               -  Post-menopausal: defined as aged more than 50 years and amenorrheic for at least
                  12 months following cessation of all exogenous hormonal treatments.

               -  Documentation of irreversible surgical sterilization by hysterectomy, bilateral
                  oophorectomy, or bilateral salpingectomy, but not tubal ligation.

               -  Women under 50 years-of-age will be considered postmenopausal if they have been
                  amenorrheic for at least 12 months following the cessation of exogenous hormonal
                  treatments, and have serum follicle-stimulating hormone and luteinizing hormone
                  levels in the postmenopausal range for the institution.

          8. Male patients should be willing to use barrier contraception for the duration of the
             study and for 3 months after treatment discontinuation.

          9. Ability to swallow and retain oral medication.

        Additional Inclusion Criteria for Phase 1a Arms AA and EA.

        1. Patients in Arms AA and EA must have metastatic prostate cancer with histological or
        cytological confirmation. Note: Patient may have bone only metastatic disease.

          -  Patients must be castrate-resistant (i.e., developed progression of metastases
             following surgical castration or during medical androgen ablation therapy). (Patients
             receiving medical castration therapy with gonadotropin-releasing hormone analogues
             should continue this treatment during this study.)

          -  Patients must have received prior treatment with one of the hormonal agents
             abiraterone, enzalutamide or apalutamide. Patients who received prior apalutamide will
             be allocated to abiraterone. Only patients with one prior hormonal agent will be
             permitted. Note: Prior chemotherapy is allowed but not required.

          -  Patients must have evidence of disease progression.

        Additional Inclusion Criteria for Phase 1a Arm CA

        1. Patients in Arm CA must have an histologically/cytologically confirmed advanced solid
        tumor malignancy that has received and progressed on standard-of-care therapy(ies).

        Additional Inclusion Criteria for Phase 1a Arms CB and CC

        1. Patients in Arms CB and CC may have a metastatic prostate cancer with histological or
        cytological confirmation:

          -  Patient must be castrate-resistant (i.e., developed progression of metastases
             following surgical castration or during medical androgen ablation therapy). Patients
             receiving medical castration therapy with gonadotropin-releasing hormone analogues
             should continue this treatment during this study. Note: Patient with prostate cancer
             may have bone-only metastatic disease.

          -  Patient must have-evidence of disease progression. Or

          -  Patients in Cohort CB must have a histologically/cytologically confirmed advanced
             solid tumor malignancy that has received and progressed on standard-of-care
             therapy(ies).

        Or

        • Patients in Cohort CC should have a histologically/cytologically confirmed advanced solid
        tumor malignancy suitable for treatment with docetaxel.

        Additional Inclusion Criteria for Phase 1b

          1. Patients must have disease that is suitable for repeated measurement, either: a) at
             least one lesion that can be accurately assessed at baseline by computed tomography
             (CT), magnetic resonance imaging (MRI) or X-ray, that is suitable for repeated
             measurement (RECIST v1.1), or b) for patients with mCRPC (Arms I and J), patients must
             have measurable PSA above normal limits (per local ranges).

          2. A minimum of 10 patients with mCRPC, CRC and 'Other' tumors will be required to have a
             site of disease that is safely accessible for biopsy (paired) upon enrollment.
             Accessible lesions are defined as those which are biopsiable (at screening) and
             amenable to repeat biopsy (after 2 weeks of monotherapy), unless clinically
             contraindicated. In the case that the second sample is not taken, the patient will
             remain in the study and there will be no penalty or loss of benefit to the patient and
             they will not be excluded from other aspects of the study. The tumor-specific cohorts
             will be closely monitored to ensure the desired number of biopsiable patients are
             enrolled. The requirement for biopsies must be made clear to each patient at the time
             of initial approach by the Investigator.

          3. For post immunotherapy patients with NSCLC (Arms F and G) all of the following must
             apply:

               -  Patients must have advanced or metastatic NSCLC with histological or cytological
                  confirmation. Patients with known EGFR-activating mutations or ALK rearrangements
                  are excluded.

               -  Patient must have previously received one (but no more than one) line of previous
                  therapy with an anti-PD-1/PD-L1 mAb therapy either alone or in combination and
                  have either progressed or responded and then stopped responding.

          4. For other post-immunotherapy patients (Arm H) all of the following must apply:

               -  Patients must have an immune checkpoint resistant malignancy (for example, RCC,
                  head and neck carcinoma, or MSI high cancers which have approved settings for
                  anti-PD1 treatment), confirmed histologically or cytologically.

               -  Patients must have previously received at least one line (and not more than 2
                  lines) of previous therapy with an anti-PD-1/PD-L1 mAb therapy, either alone or
                  in combination and have either progressed or responded and then stopped
                  responding.

          5. For immune checkpoint naïve CRPC patients (Arms I and J) all of the following must
             apply:

               -  Patients must have metastatic prostate cancer with histological or cytological
                  confirmation.

               -  Patients must be castrate-resistant (i.e., developed progression of metastases
                  following surgical castration or during medical androgen ablation therapy).
                  Patients receiving medical castration therapy with gonadotropin-releasing hormone
                  analog should continue this treatment during this study.

               -  Patients must have previously received and progressed on standard-of-care
                  therapy(ies).

               -  Approximately 60 out of 80 patients with mCRPC enrolled must have measurable
                  disease (approximately 30 out of 40 patients in each of the mCRPC arms I and J)
                  that is suitable for repeated measurement (RECIST v1.1). Enrollment will be
                  monitored to ensure the required number of patients with measurable disease enter
                  the study.

          6. For immune checkpoint naïve patients (Arms K and KD) all of the following must apply:

               -  Patients must have immune checkpoint naïve histologically/cytologically confirmed
                  advanced or metastatic colorectal carcinoma (CRC).

               -  Patients must have previously received and progressed on at least 1 prior
                  chemotherapy regimen.

          7. For other immune checkpoint naïve tumor patients (Arm L) all of the following must
             apply:

               -  Patients with other immune checkpoint naïve histologically/ cytologically
                  confirmed advanced solid tumor type that has received and progressed on
                  standard-of-care therapy(ies).

        Exclusion Criteria

          1. Treatment with any of the following:

               -  Nitrosourea or mitomycin C within 6 weeks of the first dose.

               -  Any systemic anti-cancer chemotherapy, small molecule, biologic, or hormonal
                  agent from a previous treatment regimen or clinical study within 21 days or 5
                  half-lives (whichever is longer). At least 7 days must have elapsed between the
                  last dose of such agent and the first dose of study drug. EXCEPTION:
                  Androgen-deprivation therapy is permitted for patients with prostate cancer.

               -  Enrollment into another therapeutic clinical trial. EXCEPTION: Patients are
                  allowed to participate in investigational imaging or non-therapeutic studies.

               -  Patient has had Rx or non-Rx drugs or other products known to be sensitive BCRP
                  or OAT1 substrates or to be potent inhibitors/inducers of CYP1A2, which cannot be
                  discontinued 2 weeks prior to Day 1 of dosing and withheld throughout the study
                  until 2 weeks after the last dose of AZD4635.

               -  Herbal preparations/medications are not allowed throughout the study, including
                  but not limited to St. John's Wort, kava, ephedra (ma huang), gingko biloba,
                  dehydroepiandrosterone, yohimbe, saw palmetto, and ginseng. Patients should stop
                  using these herbal medications 7 days prior to the first dose of AZD4635.

               -  Patient may not be assigned to abiraterone acetate arms if co-administration of a
                  strong CYP3A4 or a CYP2D6 substrate with a narrow therapeutic index is required
                  during study treatment.

               -  Patient may not be assigned to enzalutamide arms if requires co-administration of
                  strong CYP2C8, strong or moderate CYP3A4 or CYP2C8 inducers, CYP3A4, CYP2C9, and
                  CYP2C19 substrates during study treatment.

               -  Ongoing treatment with Coumadin.

               -  Concomitant medications with another A1R antagonist that would increase risk of
                  seizure (e.g., theophylline or aminophylline).

               -  AZD4635 in the present study (i.e., dosing with AZD4635 previously initiated in a
                  different arm in this study), or prior therapy with AZD4635 or any other A2AR
                  antagonist.

               -  Ongoing corticosteroid use. NOTE: mCRPC patients assigned to an arm with
                  abiraterone acetate treatment should take prednisone as prescribed for
                  glucocorticoid replacement therapy and patients assigned to the docetaxel arm
                  should take prophylactic dexamethasone (or equivalent) to prevent severe
                  hypersensitivity reactions.

               -  Major surgery (excluding placement of vascular access) within 4 weeks of the
                  first dose of study treatment.

               -  Radiotherapy with a wide field of radiation within 4 weeks or radiotherapy with a
                  limited field of radiation for palliation within 2 weeks of the first dose of
                  study treatment.

          2. Patient with prior history of myocardial infarction, transient ischemic attack, or
             stroke within the past 3 months prior to the scheduled first dose of oleclumab
             treatment (Arm CB).

          3. With the exception of alopecia, any unresolved toxicities from prior therapy greater
             than CTCAE Grade 1 at the time of starting study treatment.

          4. History of seizures, central nervous system tumors or CNS metastasis. Due to the
             incidence of silent CNS metastases in patients with advanced NSCLC, such patients must
             undergo mandatory screening with brain MRI or CT scan to determine eligibility.

          5. Significant mental illness in the 4-week period preceding drug administration.

          6. As judged by the investigator, any evidence of severe or uncontrolled systemic
             disease, including uncontrolled hypertension, active bleeding diatheses, or active
             infection, including hepatitis B, hepatitis C, and human immunodeficiency virus.
             Screening for chronic conditions is not required.

          7. Any of the following cardiac criteria:

               -  Mean resting corrected QT interval (QTcF) >470 msec obtained from 3 ECGs.

               -  Any clinically important abnormalities in rhythm, conduction, or morphology of
                  resting ECGs, e.g., complete left bundle branch block, third degree heart block.

               -  Any factors that increase the risk of QTc prolongation or risk of arrhythmic
                  events such as heart failure, hypokalemia, congenital long QT syndrome, family
                  history of long QT syndrome or unexplained sudden death under 40 years-of-age, or
                  any concomitant medication known to prolong the QT interval

               -  Ejection fraction < 55% or less than the lower limit of normal of the
                  institutional standard.

          8. Inadequate bone marrow reserve or organ function as demonstrated by any of the
             following laboratory values:

               -  Absolute neutrophil count < 1.5 x 10 (exp9)/L

               -  Platelet count < 100 x 10 (exp9)/L

               -  Hemoglobin <90 g/L

               -  ALT and/or AST >2.5 times the upper limit of normal (ULN) if no demonstrable
                  liver metastases or >5 times ULN in the presence of liver metastases

               -  Total bilirubin >1.5 times ULN

               -  Creatinine >1.5 times ULN concurrent with creatinine clearance <50 mL/min

          9. Refractory nausea and vomiting, chronic gastrointestinal diseases, or previous
             significant bowel resection that would preclude adequate absorption of AZD4635.

         10. Any patient with open oral ulceration(s) should avoid dosing with AZD4635 oral
             suspension.

         11. Patients with severe hepatic impairment (Child-Pugh Class C) are not permitted to
             enroll in the mCRPC plus hormone arms containing abiraterone acetate.

         12. Organ transplant that requires the use of immunosuppressive treatment.

         13. Active or prior documented autoimmune or inflammatory disorders (including
             inflammatory bowel disease [e.g., colitis, Crohn's disease], diverticulitis, celiac
             disease, systemic lupus erythematous, Wegner's syndrome, myasthenia gravis, Grave's
             disease, rheumatoid arthritis, hypophysitis, uveitis, autoimmune pneumonitis,
             autoimmune nephritis or nephropathy, etc.) within the past 3 years prior to the start
             of treatment. The following are exceptions to this criterion:

               -  Vitiligo or alopecia.

               -  Hypothyroidism (e.g., following Hashimoto's disease) stable on hormone
                  replacement.

               -  Psoriasis or eczema not requiring systemic treatment.

         14. Patients with prior ≥ Grade 3, serious, or life threatening immune-mediated reactions
             following prior anti-PD-1 or other immune-oncology therapies.

         15. History of hypersensitivity to AZD4635 or drugs with a similar chemical structure or
             class to AZD4635.

         16. Judgment by the Investigator or the Medical Monitor that the patient should not
             participate in the study if the patient is unlikely to comply with study procedures,
             restrictions, and/or requirements.
      
Maximum Eligible Age:130 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:The incidence of Dose-Limiting Toxicities (DLTs) in patients receiving AZD4635 monotherapy orally.
Time Frame:3 weeks (One Cycle)
Safety Issue:
Description:A Bayesian Logistic Regression Model (BLRM) based approach will be used to identify the set of AZD4635 doses where the incidence of DLTs is no larger than 33%. In each arm, up to 3 patients will be initially assessed. The dose will be escalated to the next higher dose level if all 3 patients in the previous dose level complete the DLT evaluation period without a DLT. Following the first DLT, the BLRM model will be run and the output made available to the safety review committee (SRC) to guide further dosing decisions. Each dose cohort will include a maximum of 6 patients.

Secondary Outcome Measures

Measure:Peak plasma concentration (Cmax) of AZD4635 after single-dose administration in Cycle 0
Time Frame:Samples will be collected at pre-specified time points for up to one-week following a single-dose of AZD4635 (Cycle 0). The multiple-dose PK sampling will commence with Cycle 1 Day 1.
Safety Issue:
Description:The plasma concentration of AZD4635 will be determined by inspection of the concentration-time profile. Intensive pharmacokinetic sampling with matched ECGs is required in Phase 1a and in NSCLC Cohorts and mCRPC Cohorts in the monotherapy portion of the study. After the pharmacokinetic profile has been sufficiently characterised, sample collection in the mCRPC and NSCLC expansion cohorts may be limited to coincide with ECG-matched time points in patients being newly enrolled. Sparse sample collections are required from patients in CRC, Post-IO Other, and IO-Naïve Other cohorts.
Measure:Time to peak plasma concentration (tmax) of AZD4635 after single-dose administration in Cycle 0
Time Frame:Samples will be collected at pre-specified time points for up to one-week following a single-dose of AZD4635 (Cycle 0). The multiple-dose PK sampling will commence with Cycle 1 Day 1.
Safety Issue:
Description:The plasma concentration of AZD4635 will be determined by inspection of the concentration-time profile. Intensive pharmacokinetic sampling with matched ECGs is required in Phase 1a and in NSCLC Cohorts and mCRPC Cohorts in the monotherapy portion of the study. After the pharmacokinetic profile has been sufficiently characterised, sample collection in the mCRPC and NSCLC expansion cohorts may be limited to coincide with ECG-matched time points in patients being newly enrolled. Sparse sample collections are required from patients in CRC, Post-IO Other, and IO-Naïve Other cohorts.
Measure:Terminal elimination rate constant (λz) of AZD4635 after single-dose administration in Cycle 0
Time Frame:Samples will be collected at pre-specified time points for up to one-week following a single-dose of AZD4635 (Cycle 0). The multiple-dose PK sampling will commence with Cycle 1 Day 1.
Safety Issue:
Description:The plasma concentration of AZD4635 will be determined by inspection of the concentration-time profile. Intensive pharmacokinetic sampling with matched ECGs is required in Phase 1a and in NSCLC Cohorts and mCRPC Cohorts in the monotherapy portion of the study. After the pharmacokinetic profile has been sufficiently characterised, sample collection in the mCRPC and NSCLC expansion cohorts may be limited to coincide with ECG-matched time points in patients being newly enrolled. Sparse sample collections are required from patients in CRC, Post-IO Other, and IO-Naïve Other cohorts.
Measure:Terminal elimination half-life (t½λz) of AZD4635 after single-dose administration in Cycle 0
Time Frame:Samples will be collected at pre-specified time points for up to one-week following a single-dose of AZD4635 (Cycle 0). The multiple-dose PK sampling will commence with Cycle 1 Day 1.
Safety Issue:
Description:The plasma concentration of AZD4635 will be determined by inspection of the concentration-time profile. Intensive pharmacokinetic sampling with matched ECGs is required in Phase 1a and in NSCLC Cohorts and mCRPC Cohorts in the monotherapy portion of the study. After the pharmacokinetic profile has been sufficiently characterised, sample collection in the mCRPC and NSCLC expansion cohorts may be limited to coincide with ECG-matched time points in patients being newly enrolled. Sparse sample collections are required from patients in CRC, Post-IO Other, and IO-Naïve Other cohorts.
Measure:Area under the plasma concentration-time curve following single dose administration of AZD4635 in Cycle 0
Time Frame:Samples will be collected at pre-specified time points for up to one-week following a single-dose of AZD4635 (Cycle 0). The multiple-dose PK sampling will commence with Cycle 1 Day 1.
Safety Issue:
Description:The plasma concentration of AZD4635 will be determined by inspection of the concentration-time profile. Intensive pharmacokinetic sampling with matched ECGs is required in Phase 1a and in NSCLC Cohorts and mCRPC Cohorts in the monotherapy portion of the study. After the pharmacokinetic profile has been sufficiently characterised, sample collection in the mCRPC and NSCLC expansion cohorts may be limited to coincide with ECG-matched time points in patients being newly enrolled. Sparse sample collections are required from patients in CRC, Post-IO Other, and IO-Naïve Other cohorts.
Measure:Apparent plasma clearance (CL/F) after single-dose administration of AZD4635 in Cycle 0
Time Frame:Samples will be collected at pre-specified time points for up to one-week following a single-dose of AZD4635 (Cycle 0). The multiple-dose PK sampling will commence with Cycle 1 Day 1.
Safety Issue:
Description:The plasma concentration of AZD4635 will be determined by inspection of the concentration-time profile. Intensive pharmacokinetic sampling with matched ECGs is required in Phase 1a and in NSCLC Cohorts and mCRPC Cohorts in the monotherapy portion of the study. After the pharmacokinetic profile has been sufficiently characterised, sample collection in the mCRPC and NSCLC expansion cohorts may be limited to coincide with ECG-matched time points in patients being newly enrolled. Sparse sample collections are required from patients in CRC, Post-IO Other, and IO-Naïve Other cohorts.
Measure:Apparent volume of distribution (Vz/F) after single-dose administration of AZD4635 in Cycle 0
Time Frame:Samples will be collected at pre-specified time points for up to one-week following a single-dose of AZD4635 (Cycle 0). The multiple-dose PK sampling will commence with Cycle 1 Day 1.
Safety Issue:
Description:The plasma concentration of AZD4635 will be determined by inspection of the concentration-time profile. Intensive pharmacokinetic sampling with matched ECGs is required in Phase 1a and in NSCLC Cohorts and mCRPC Cohorts in the monotherapy portion of the study. After the pharmacokinetic profile has been sufficiently characterised, sample collection in the mCRPC and NSCLC expansion cohorts may be limited to coincide with ECG-matched time points in patients being newly enrolled. Sparse sample collections are required from patients in CRC, Post-IO Other, and IO-Naïve Other cohorts.
Measure:Mean residence time (MRT) of AZD4635 after single-dose administration in Cycle 0
Time Frame:Samples will be collected at pre-specified time points for up to one-week following a single-dose of AZD4635 (Cycle 0). The multiple-dose PK sampling will commence with Cycle 1 Day 1.
Safety Issue:
Description:The plasma concentration of AZD4635 will be determined by inspection of the concentration-time profile. Intensive pharmacokinetic sampling with matched ECGs is required in Phase 1a and in NSCLC Cohorts and mCRPC Cohorts in the monotherapy portion of the study. After the pharmacokinetic profile has been sufficiently characterised, sample collection in the mCRPC and NSCLC expansion cohorts may be limited to coincide with ECG-matched time points in patients being newly enrolled. Sparse sample collections are required from patients in CRC, Post-IO Other, and IO-Naïve Other cohorts.
Measure:Renal clearance (CLR) of AZD4635 after single-dose administration in Cycle 0
Time Frame:Samples will be collected at pre-specified time points for up to one-week following a single-dose of AZD4635 (Cycle 0). The multiple-dose PK sampling will commence with Cycle 1 Day 1.
Safety Issue:
Description:The plasma concentration of AZD4635 will be determined by inspection of the concentration-time profile. Intensive pharmacokinetic sampling with matched ECGs is required in Phase 1a and in NSCLC Cohorts and mCRPC Cohorts in the monotherapy portion of the study. After the pharmacokinetic profile has been sufficiently characterised, sample collection in the mCRPC and NSCLC expansion cohorts may be limited to coincide with ECG-matched time points in patients being newly enrolled. Sparse sample collections are required from patients in CRC, Post-IO Other, and IO-Naïve Other cohorts.
Measure:Amount of AZD4635 excreted unchanged in urine (Ae) after single-dose administration in Cycle 0
Time Frame:Urine will be collected and pooled at specific intervals: pre-dose (spot urine), 0 to 4 hours, 4 to 8 hours, and 8 to 24 hours.
Safety Issue:
Description:The amount of AZD4635 (and metabolites) in urine will be determined in all patients. Pooled collections of urine 0 to 4 hours post dose, 4 to 8 hours post dose, and 8 to 24 hours post dose. Patients will collect all urine at home and bring the 8 to 24 hour pooled collection to the clinic. The total volume of each pooled sample will be recorded after which a 10 mL aliquot will be taken for analysis.
Measure:Fraction of AZD4635 excreted unchanged in urine (fe) after single-dose administration in Cycle 0
Time Frame:Urine will be collected and pooled at specific intervals: pre-dose (spot urine), 0 to 4 hours, 4 to 8 hours, and 8 to 24 hours.
Safety Issue:
Description:The amount of AZD4635 (and metabolites) in urine will be determined in all patients. Pooled collections of urine 0 to 4 hours post dose, 4 to 8 hours post dose, and 8 to 24 hours post dose. Patients will collect all urine at home and bring the 8 to 24 hour pooled collection to the clinic. The total volume of each pooled sample will be recorded after which a 10 mL aliquot will be taken for analysis.
Measure:Peak plasma concentration of AZD4635 at steady state (Cmax, ss) following multiple-doses on Cycle 1 Day 15 in monotherapy arms and Cycle 1 Day 1 and Cycle 3 Day 15 in combination therapy arms.
Time Frame:Samples will be collected at pre-specified time points in the multiple-dose portion of the study beginning with Cycle 1 Day 1. Sampling be done on 1 of 3 schedules: i) Intensive sampling, ii) ECG-matched sampling, or iii) Sparse sampling.
Safety Issue:
Description:The plasma concentration of AZD4635 will be determined by inspection of the concentration-time profile. Intensive pharmacokinetic sampling with matched ECGs is required in Phase 1a and in NSCLC Cohorts and mCRPC Cohorts in the monotherapy portion of the study. After the pharmacokinetic profile has been sufficiently characterised, sample collection in the mCRPC and NSCLC expansion cohorts may be limited to coincide with ECG-matched time points in patients being newly enrolled. Sparse sample collections are required from patients in CRC, Post-IO Other, and IO-Naïve Other cohorts.
Measure:Time to peak plasma concentration of AZD4635 at steady state (tmax, ss) following multiple-doses on Cycle 1 Day 15 in monotherapy arms and Cycle 1 Day 1 and Cycle 3 Day 15 in combination therapy arms.
Time Frame:Samples will be collected at pre-specified time points in the multiple-dose portion of the study beginning with Cycle 1 Day 1. Sampling be done on 1 of 3 schedules: i) Intensive sampling, ii) ECG-matched sampling, or iii) Sparse sampling.
Safety Issue:
Description:The plasma concentration of AZD4635 will be determined by inspection of the concentration-time profile. Intensive pharmacokinetic sampling with matched ECGs is required in Phase 1a and in NSCLC Cohorts and mCRPC Cohorts in the monotherapy portion of the study. After the pharmacokinetic profile has been sufficiently characterised, sample collection in the mCRPC and NSCLC expansion cohorts may be limited to coincide with ECG-matched time points in patients being newly enrolled. Sparse sample collections are required from patients in CRC, Post-IO Other, and IO-Naïve Other cohorts.
Measure:Minimum plasma concentration of AZD4635 at steady state (Cmin, ss) following multiple-doses on Cycle 1 Day 15 in monotherapy arms and Cycle 1 Day 1 and Cycle 3 Day 15 in combination therapy arms.
Time Frame:Samples will be collected at pre-specified time points in the multiple-dose portion of the study beginning with Cycle 1 Day 1. Sampling be done on 1 of 3 schedules: i) Intensive sampling, ii) ECG-matched sampling, or iii) Sparse sampling.
Safety Issue:
Description:The plasma concentration of AZD4635 will be determined by inspection of the concentration-time profile. Intensive pharmacokinetic sampling with matched ECGs is required in Phase 1a and in NSCLC Cohorts and mCRPC Cohorts in the monotherapy portion of the study. After the pharmacokinetic profile has been sufficiently characterised, sample collection in the mCRPC and NSCLC expansion cohorts may be limited to coincide with ECG-matched time points in patients being newly enrolled. Sparse sample collections are required from patients in CRC, Post-IO Other, and IO-Naïve Other cohorts.
Measure:Area under the plasma concentration-time curve within the dosing interval (AUCtau) following multiple-doses on Cycle 1 Day 15 in monotherapy arms and Cycle 1 Day 1 and Cycle 3 Day 15 in combination therapy arms.
Time Frame:Samples will be collected at pre-specified time points in the multiple-dose portion of the study beginning with Cycle 1 Day 1. Sampling be done on 1 of 3 schedules: i) Intensive sampling, ii) ECG-matched sampling, or iii) Sparse sampling.
Safety Issue:
Description:The plasma concentration of AZD4635 will be determined by inspection of the concentration-time profile. Intensive pharmacokinetic sampling with matched ECGs is required in Phase 1a and in NSCLC Cohorts and mCRPC Cohorts in the monotherapy portion of the study. After the pharmacokinetic profile has been sufficiently characterised, sample collection in the mCRPC and NSCLC expansion cohorts may be limited to coincide with ECG-matched time points in patients being newly enrolled. Sparse sample collections are required from patients in CRC, Post-IO Other, and IO-Naïve Other cohorts.
Measure:Apparent plasma clearance at steady state (CLss/F) following multiple-doses on Cycle 1 Day 15 in monotherapy arms and Cycle 1 Day 1 and Cycle 3 Day 15 in combination therapy arms.
Time Frame:Samples will be collected at pre-specified time points in the multiple-dose portion of the study beginning with Cycle 1 Day 1. Sampling be done on 1 of 3 schedules: i) Intensive sampling, ii) ECG-matched sampling, or iii) Sparse sampling.
Safety Issue:
Description:The plasma concentration of AZD4635 will be determined by inspection of the concentration-time profile. Intensive pharmacokinetic sampling with matched ECGs is required in Phase 1a and in NSCLC Cohorts and mCRPC Cohorts in the monotherapy portion of the study. After the pharmacokinetic profile has been sufficiently characterised, sample collection in the mCRPC and NSCLC expansion cohorts may be limited to coincide with ECG-matched time points in patients being newly enrolled. Sparse sample collections are required from patients in CRC, Post-IO Other, and IO-Naïve Other cohorts.
Measure:Extent of accumulation of AZD4635 (Rac) after multiple dosing
Time Frame:Samples will be collected at pre-specified time points in the multiple-dose portion of the study beginning with Cycle 1 Day 1. Sampling be done on 1 of 3 schedules: i) Intensive sampling, ii) ECG-matched sampling, or iii) Sparse sampling.
Safety Issue:
Description:The plasma concentration of AZD4635 will be determined by inspection of the concentration-time profile. Intensive pharmacokinetic sampling with matched ECGs is required in Phase 1a and in NSCLC Cohorts and mCRPC Cohorts in the monotherapy portion of the study. After the pharmacokinetic profile has been sufficiently characterised, sample collection in the mCRPC and NSCLC expansion cohorts may be limited to coincide with ECG-matched time points in patients being newly enrolled. Sparse sample collections are required from patients in CRC, Post-IO Other, and IO-Naïve Other cohorts.
Measure:Time dependency of AZD4635 pharmacokinetic parameters (TCP) after multiple dosing.
Time Frame:Samples will be collected at pre-specified time points in the multiple-dose portion of the study beginning with Cycle 1 Day 1. Sampling be done on 1 of 3 schedules: i) Intensive sampling, ii) ECG-matched sampling, or iii) Sparse sampling.
Safety Issue:
Description:The plasma concentration of AZD4635 will be determined by inspection of the concentration-time profile. Intensive pharmacokinetic sampling with matched ECGs is required in Phase 1a and in NSCLC Cohorts and mCRPC Cohorts in the monotherapy portion of the study. After the pharmacokinetic profile has been sufficiently characterised, sample collection in the mCRPC and NSCLC expansion cohorts may be limited to coincide with ECG-matched time points in patients being newly enrolled. Sparse sample collections are required from patients in CRC, Post-IO Other, and IO-Naïve Other cohorts.
Measure:The concentration of durvalumab and anti-drug antibody in plasma when given in combination with AZD4635
Time Frame:Preinfusion and end of infusion on Day 1 of Cycles 2 and 5. Preinfusion of Day 1 of Cycles 3 and 8 and 90-days after the last dose of durvalumab.
Safety Issue:
Description:Plasma concentration of durvalumab and anti-drug antibody will be determined by inspection of the concentration-time profile. The date and time of collection of each sample will be recorded.
Measure:The effect of AZD4635 on QTc interval
Time Frame:In screening and on Days 1, 2 and 15 in Cycle 1, Day 1 of each cycle thereafter, and at the end of treatment and at each progression-free follow-up visit.
Safety Issue:
Description:Twelve-lead ECGs will be obtained after the patient has been resting supine for at least 10 minutes. For each time point 3 ECG recordings should be taken at about 2- to 5 minute intervals.
Measure:Tumour Response
Time Frame:Tumour response will be assessed 6 weeks after the start of treatment and then every 8 weeks thereafter up to 1 year.
Safety Issue:
Description:Categorization of objective tumour response assessment will be based on the RECIST Version 1.1 guidelines for response (CR (complete response), PR (partial response), SD (stable disease), and PD (progressive disease). For patients who only have non-measurable disease at baseline, categorization of objective tumour response assessment will be based on the RECIST Version 1.1 guideline for response for non-target lesions (NTLs): CR, PD, and Non CR/Non PD.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:AstraZeneca

Trial Keywords

  • AZD4635
  • durvalumab
  • oleclumab
  • docetaxel
  • non-small cell lung cancer
  • advanced solid malignancies
  • prostate cancer
  • colorectal cancer
  • abiraterone acetate
  • enzalutamide

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