Clinical Trials /

AZD5153 in Patients With Relapsed or Refractory Solid Tumors, Including Lymphomas

NCT03205176

Description:

This is a first-time-in-man (FTIM) multicenter, dose escalation study designed to investigate the safety, pharmacokinetics, and pharmacodynamics of AZD5153 in patients with malignant solid tumors, including lymphomas.

Related Conditions:
  • Lymphoma
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: AZD5153 in Patients With Relapsed or Refractory Solid Tumors, Including Lymphomas
  • Official Title: A Phase I, Multicenter Dose-Escalation Study to Assess the Tolerability, Pharmacokinetics and Preliminary Anti-tumor Activity of AZD5153 in Patients With Relapsed/Refractory Malignant Solid Tumors, Including Lymphomas

Clinical Trial IDs

  • ORG STUDY ID: D6520C00001
  • SECONDARY ID: REFMAL 495
  • NCT ID: NCT03205176

Conditions

  • Malignant Solid Tumors
  • Lymphoma
  • Ovarian Cancer

Interventions

DrugSynonymsArms
AZD5153AZD5153 Monotherapy
OlaparibLynparzaAZD5153 + Olaparib Combination Therapy

Purpose

This is a first-time-in-man (FTIM) multicenter, dose escalation study designed to investigate the safety, pharmacokinetics, and pharmacodynamics of AZD5153 in patients with malignant solid tumors, including lymphomas.

Detailed Description

      The trial will be conducted in two parts, dose escalation and dose expansion. AZD5153 will be
      investigated as a monotherapy and in combination with olaparib.

      AZD5153 monotherapy (dose escalation):

      This part of the study will enroll patients with advanced solid malignancies, including
      lymphoma, and test safety and tolerability of AZD5153 administered as a monotherapy. A
      Bayesian Continual Reassessment Method (CRM) will be applied to approximately 6 cohorts of
      patients. Each cohort will enroll at least 3 and up to 6 evaluable patients on ascending oral
      doses of AZD5153 on continuous cycles of 21 days. The dose-limiting toxicity (DLT) evaluation
      period will extend until the end of Cycle 1 (21 days). The dose escalation will proceed by
      two-fold increments or through lower doses suggested by the CRM until an MTD as defined by
      dose-limiting toxicity is reached.

      Single daily (QD) and twice daily (BID) dosing schedules will be explored in the monotherapy
      cohort. Additional dose levels or dosing schedules may be evaluated and recommended by study
      Safety Review Committee (SRC) based on the emerging PK and safety data.

      When the AZD5153 monotherapy MTD is established, an expansion cohort consisting of up to 12
      additional evaluable patients may be enrolled to confirm the safety and tolerability of the
      MTD. The dose expansion will be initiated and will enroll patients with histologically or
      cytologically confirmed platinum resistant or platinum-refractory high grade serous ovarian
      (HGSO) cancer.

      Mandatory tumor biopsies at screening for ovarian cancer patients will be required for
      patient enrollment in the MTD dose expansion cohort. Optional on-treatment biopsies will be
      requested from consenting patients in the ovarian expansion cohort.

      AZD5153 + olaparib combination (dose escalation):

      Dose escalation of AZD5153 in combination with olaparib will also be investigated while the
      AZD5153 monotherapy dose escalation is ongoing and prior to determination of a monotherapy
      MTD. In the combination dose escalation part, patients with platinum-resistant or
      platinum-refractory HGS ovarian cancer will be dosed with ascending doses of AZD5153 in
      combination with 300 mg of olaparib BID, the recommended dose in the FDA-approved labeling.

      The starting dose of AZD5153 in combination with olaparib will be a dose that has been shown
      to be safe and tolerated in monotherapy and has been chosen because clinical exposure
      achieved at this dose is equivalent to preclinical exposure causing tumour growth inhibition
      in animal models. If the starting dose in combination with olaparib is safe and tolerated,
      the dose of AZD5153 will be escalated, using the same method as for the monotherapy part of
      the study, keeping the olaparib dose fixed at 300 mg BID. Intermittent schedules as well as
      continuous BID or QD dosing of AZD5153 in combination with 300 mg BID olaparib might be
      tested until a safe and tolerated combination dose and schedule is determined. However, the
      total dose per cycle of AZD5153 used in combination with olaparib won't exceed the total dose
      per cycle that has been shown to be safe and tolerated as a monotherapy, and won't be higher
      than the dose declared to be the monotherapy MTD. If intermittent dosing is explored then the
      CRM will consider cumulative dosing rather than daily dosing.

      AZD5153 and olaparib will be administered in continuous cycles of 21 days. Before starting
      concomitant administration of the two agents, a single dose of AZD5153 (designated Cycle 0
      PK) may be administered to patients enrolled in this portion of the study to better
      characterize the AZD5153 pharmacokinetic (PK) parameters before the addition of olaparib.
      Additional doses and schedule of AZD5153 + olaparib might be tested based on emerging PK and
      safety data as recommended by the SRC. The combination dose escalation part will run in
      parallel with the AZD5153 monotherapy part (dose escalation and expansion) and will continue
      until a safe and tolerated combination dose of the two agents is declared.

      Mandatory paired tumor biopsies at screening and on-treatment will be required for patients
      enrolled into the combination dose escalation in order to assess BRD4 copy number as well as
      exploratory homologous recombination deficiency (HRD) markers and other exploratory markers.

      The dose-limiting toxicity (DLT) evaluation period will last from Cycle 0 until the end of
      Cycle 1 (22 days). Each cohort will enroll 3 and up to 6 evaluable patients at each
      combination dose level with the expectation of dosing approximately 18 patients in the
      combination part of this study. However, the exact number of cohorts will depend on safety
      and tolerability data emerging from the monotherapy part of the study as well as the
      combination cohorts already dosed. Expansion cohorts at a tolerated combination dose might be
      added based on safety and tolerability data generated during the combination dose escalation
      part of the study.
    

Trial Arms

NameTypeDescriptionInterventions
AZD5153 MonotherapyExperimentalPatients will be enrolled in cohorts of up to 6 patients each in a dose escalating scheme to determine MTD. AZD5153 will be taken once per day (QD) or two times per day (BID) for 21 days as an oral capsule.
  • AZD5153
AZD5153 + Olaparib Combination TherapyExperimentalPatients will be enrolled in cohorts of up to 6 patients each in a dose escalating scheme to determine MTD. AZD5153 will be taken as oral capsules BID in combination with 300 mg olaparib BID for 21 days.
  • AZD5153
  • Olaparib

Eligibility Criteria

        Inclusion Criteria for all Patients:

          1. Patient must be able to understand the nature of the study and provide a signed and
             dated, written informed consent prior to any study specific procedures, sampling or
             analyses.

          2. Patients should have the ability and willingness to comply with the study and
             follow-up procedures.

          3. Patients must have a solid tumor that is refractory to or intolerant of existing
             therapies known to provide clinical benefit for their clinical condition.

          4. Age ≥ 18

          5. Adequate organ function, determined by:

               -  Absolute neutrophil count (ANC) ≥ 1.5 X10^9/L

               -  Platelets ≥ 100 X10^9/L

               -  Hemoglobin ≥ 9g/dL

               -  aPTT ≤1.5 x ULN

               -  Total bilirubin ≤ 1.5 mg/dL

               -  ALT and AST ≤ 2.5 x ULN if no liver involvement or ≤ 5 x ULN with liver
                  involvement

               -  Creatinine <1.5 times ULN concurrent with creatinine clearance >50 mL/min
                  (measured or calculated by Cockcroft and Gault equation); confirmation of
                  creatinine clearance is only required when creatinine is >1.5 times ULN

          6. Normotensive or well controlled blood pressure (BP) (<140/90), with or without current
             antihypertensive treatment. If there is a diagnosis or history of hypertension,
             patient must have adequately controlled BP on a maximum of 2 antihypertensive
             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 antihypertensive medications be followed by a cardiologist or
             a primary care physician for management of BP while on the study. Patients on a
             hypertensive medication must be willing and able to check and record twice daily BP
             readings for a minimum of 3 weeks.

          7. ECOG performance status of 0-1

          8. Life expectancy ≥ 3 months

          9. Ejection fraction (EF) > 50%

         10. Patients must have the ability to swallow and retain oral medication

         11. Toxicities from prior therapy greater than CTCAE Grade 1 have resolved with the
             exception of alopecia. Patients with Grade ≤ 2 neuropathy are eligible.

         12. Male patients with female partners of child-bearing potential must be willing to use
             two forms of acceptable contraception, including one barrier method, during their
             participation in this study and for 6 months after stopping study treatment. Female
             partners of child-bearing potential of male patients must use at least one of the two
             forms of acceptable contraception.

               -  Male patients must refrain from donating sperm during their participation in the
                  study and until 6 months after the last treatment.

               -  Male patients will be counselled about the utility of freezing their sperm
                  samples prior to the start of the study should they wish to father children while
                  on AZD5153 or during the 6 months after stopping AZD5153.

         13. Female patients must use two highly effective contraceptive measures. All methods of
             contraception (with the exception of total abstinence) should be used in combination
             with the use of a condom by a male sexual partner for intercourse. Female patients
             must not be breast-feeding and must have a negative pregnancy test prior to start of
             dosing if of childbearing potential or must have evidence of non-childbearing
             potential by fulfilling one of the following criteria at screening:

               -  Post-menopausal women defined as aged more than 50 years and amenorrhoeic for at
                  least 12 months following cessation of all exogenous hormonal treatment.

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

        Additional Inclusion Criteria Specific for Monotherapy Dose Escalation:

          1. Patients with histological or cytological confirmation of a malignant solid tumor
             (locally advanced or metastatic) or lymphoma (any histology) that is refractory to
             standard therapy(ies) or for which no standard therapy(ies) exists.

             - Patients with a malignant solid tumor must have at least 1 lesion that can be
             accurately measured at baseline by computed tomography (CT) scan according to Response
             Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria (Eisenhauer et al. 2009)
             and is suitable for repeated measurement.

          2. Patients with lymphoma must have documented analysis of bone marrow infiltration from
             biopsy carried out < 3 months of enrollment, or be able to undergo a new bone marrow
             biopsy if such procedure was performed > 3 months prior to enrollment.

             - Patients with a lymphoma must have at least 1 lesion that can be accurately assessed
             at baseline by CT or CT and positron emission tomography (PET) according to the Cheson
             criteria (Cheson et al 2007 and is suitable for repeated assessment.

          3. Patient must agree to the collection of formalin fixed paraffin-embedded (FFPE) blocks
             or slides from archival diagnostic histology samples, or a fresh pre-treatment biopsy
             will be accepted.

        Additional Inclusion Criteria specific for MTD monotherapy expansion and olaparib
        combination dose escalation (HGSO cancer patients):

          1. Patients with histologically or cytologically confirmed platinum-resistant OR
             platinum-refractory HGSO in the relapsed setting must have at least 1 lesion that can
             be accurately assessed at baseline by CT scan according to RECIST v1.1 criteria
             (Eisenhauer et al. 2009) and is suitable for repeated assessment. Platinum-resistant
             disease is defined by progression within 6 months following the last administered
             platinum-based regimen. Platinum-refractory disease is defined by lack of at least a
             partial response while on platinum-containing regimens.

          2. Patients will be allowed on study regardless of their BRCA mutational status.
             Information about their BRCA mutational status must be collected if patients have been
             tested as part of their standard of care.

          3. Previous response to olaparib or other PARPi is not required

          4. Patients must have at least 1 site of disease amenable to biopsy at screening, and
             must be a candidate for tumor biopsy. Patients must be willing to undergo a new tumor
             biopsy during screening. An on-treatment tumor biopsy will be mandatory in the
             olaparib combination dose escalation portion of this study, and optional from
             consenting patients in the monotherapy expansion at MTD.

          5. For the olaparib combination portion of this study, patients are required to have
             hemoglobin ≥10 g/dL at study entry.

        Exclusion Criteria:

          1. Patients who have been treated with most recent chemotherapy, radiotherapy, hormonal
             therapy, immunotherapy or investigational drugs within 21 days or 5 half-lives
             (whichever is shorter) from enrollment.

          2. Minimum wash-out period for previous PARPi therapy is at least 14 days or 5 half-lives
             whichever is shorter, or until toxicity from previous PARPi therapy has fully
             recovered.

          3. Patient received more than 5 prior lines of treatment for an advanced solid tumor
             (including HGSO cancer). Patients with lymphoma will be able to enroll without a
             restriction in the number of previous therapies received, if they otherwise meet
             eligibility criteria.

          4. Major surgery (excluding placement of vascular access) ≤ 21 days from the beginning of
             enrollment or minor surgical procedures ≤ 7 days. No waiting is required following
             implantable port and catheter placement.

          5. Patient is unable to swallow oral medications or has a gastrointestinal disorder
             (e.g., malabsorption) that would jeopardize intestinal absorption of AZD5153 and
             olaparib.

          6. Treatment with any of the following:

               -  Patient has had prescription or non-prescription drugs or other products known to
                  be strong or moderate inhibitors/inducers of CYP3A4/5, or CYP3A4/5 sensitive
                  substrates or substrates with a narrow therapeutic range, which cannot be
                  discontinued 2 weeks prior to the first day of dosing and withheld throughout the
                  study until 2 weeks after the last dose of AZD5153 and/or olaparib.

               -  Drugs that are sensitive substrates of the transporters P-gp, UGT1A1, BCRP,
                  OATP1B1, OAT3, OCT1, OCT2, MATE1 and MATE2K.

               -  Herbal preparations/medications are not allowed throughout the study. These
                  herbal medications include, but are 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 14 days prior to
                  the first dose of AZD5153 and/or olaparib.

               -  Drugs known to prolong QT interval or induce Torsades de Pointes.

          7. Refractory nausea and vomiting, previous significant bowel resection that would
             preclude adequate absorption of study drug and chronic gastrointestinal disease
             including active or prior documented inflammatory bowel disease.

          8. Patient has a history of tuberculosis.

          9. Patients receiving a live attenuated vaccine ≤28 days before the first dose of study
             drug.

         10. Spinal cord compression or brain metastases unless asymptomatic, treated and stable
             and not requiring steroids for at least 4 weeks prior to start of study treatment.

         11. A diagnosis of MDS or secondary AML (for olaparib combination dose escalation only)

         12. As judged by the Investigator, any evidence of severe or uncontrolled systemic
             diseases, including uncontrolled hypertension, active bleeding diatheses, or active
             infection including hepatitis B, hepatitis C, human immunodeficiency virus (HIV) or
             other comorbidity that renders the patient unsuitable for participation in the study.
             Screening for chronic conditions is not required.

         13. Any of the following cardiac criteria:

               -  Mean resting corrected QT interval (QTcF) >450 msec obtained from 3
                  electrocardiograms (ECGs).

               -  Any clinically important abnormalities in rhythm, conduction or morphology of
                  resting ECG 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.

         14. History of hypersensitivity to active or inactive excipients of AZD5153 and/or
             olaparib or drugs with a similar chemical structure or class to AZD5153 and/or
             olaparib.

         15. Patients with non-Hodgkin lymphoma (NHL) at high risk for developing tumor lysis
             syndrome are not eligible for the monotherapy dose escalation part of this study.

         16. Judgment by the Investigator that the patient should not participate in the study if
             the patient is unlikely to comply with study procedures, restrictions and
             requirements.

         17. Psychological, familial, sociological, or geographical conditions that do not permit
             compliance with the protocol.
      
Maximum Eligible Age:130 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of dose-limiting toxicity (DLT).
Time Frame:From the first dose of study treatment up to last day of cycle 1 (21 days)
Safety Issue:
Description:DLTs will be determined from monitoring adverse events (AEs), and abnormal laboratory tests (clinical chemistry, hematology, and urinalysis), physical examinations, vital signs (blood pressure and pulse), and electrocardiogram (ECG).

Secondary Outcome Measures

Measure:Peak plasma concentration (Cmax)
Time Frame:Samples for single dose PK will be collected at prespecified time points on Day 1, Cycle 1 pre-dose on Day 2. Multiple-dose PK will be assessed from samples taken on Days 15 and 16 of Cycle 1.
Safety Issue:
Description:The concentration of AZD5153 and its co-former in blood and plasma will be determined (Cmax will be derived).
Measure:The urine concentration of AZD5153 and its co-former (if appropriate).
Time Frame:Urine will be collected pre-dose (spot sample), and volumetrically from 0-6, 6-12, 12-24 hours on Day 1 and Day 15 of Cycle 1.
Safety Issue:
Description:Total urine volume will be measured for each interval and urine concentration of AZD5153 will be determined. A sample for the determination of 1β-hydroxy deoxycholic acid will be taken from the total urine collection at each scheduled time interval.
Measure:The effect of AZD 5153 on QTc interval.
Time Frame:ECGs will be performed at prespecified time points on Days 1 and 2 and 15 and 16 of Cycle 1.
Safety Issue:
Description:Triplicate 12-lead ECGs will be taken at screening and at prespecified times on Cycle 1 Days 1 and 2 and Days 15 and 16.
Measure:Antitumor activity of AZD5153 in patients by assessing the disease control rate (DCR).
Time Frame:Up to 1 year
Safety Issue:
Description:Investigator assessments according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1) for solid tumors or the 2007 Revised Response Criteria for Malignant Lymphoma criteria for lymphoma will be applied. The preliminary anti-tumor activity of AZD5153 in patients with ovarian carcinoma will be evaluated.
Measure:Antitumor activity of AZD5153 in patients by assessing progression free survival (PFS).
Time Frame:Up to 1 year
Safety Issue:
Description:Investigator assessments according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1) for solid tumors or the 2007 Revised Response Criteria for Malignant Lymphoma criteria for lymphoma will be applied. The preliminary anti-tumor activity of AZD5153 in patients with ovarian carcinoma will be evaluated.
Measure:Antitumor activity of AZD5153 in patients by assessing overall survival (OS).
Time Frame:Up to 1 year
Safety Issue:
Description:Investigator assessments according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1) for solid tumors or the 2007 Revised Response Criteria for Malignant Lymphoma criteria for lymphoma will be applied. The preliminary anti-tumor activity of AZD5153 in patients with ovarian carcinoma will be evaluated.
Measure:Antitumor activity of AZD5153 in patients by assessing overall response rate (ORR).
Time Frame:Up to 1 year
Safety Issue:
Description:Investigator assessments according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1) for solid tumors or the 2007 Revised Response Criteria for Malignant Lymphoma criteria for lymphoma will be applied. The preliminary anti-tumor activity of AZD5153 in patients with ovarian carcinoma will be evaluated.
Measure:Antitumor activity of AZD5153 in patients by assessing duration of response (DoR).
Time Frame:Up to 1 year
Safety Issue:
Description:Investigator assessments according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1) for solid tumors or the 2007 Revised Response Criteria for Malignant Lymphoma criteria for lymphoma will be applied. The preliminary anti-tumor activity of AZD5153 in patients with ovarian carcinoma will be evaluated.
Measure:Area under the plasma concentration versus time curve (AUC).
Time Frame:Samples for single dose PK will be collected at prespecified time points on Day 1, Cycle 1 pre-dose on Day 2. Multiple-dose PK will be assessed from samples taken on Days 15 and 16 of Cycle 1.
Safety Issue:
Description:The concentration of AZD5153 and its co-former in blood will be determined. Area under the curve is the integral of the concentration-time curve. The area under the plasma drug concentration-time curve (AUC) reflects the actual body exposure to drug after administration. The area under the curve is dependent on the rate of elimination of the drug from the body and the dose administered.
Measure:Time to reach peak plasma concentration (tmax).
Time Frame:Samples for single dose PK will be collected at prespecified time points on Day 1, Cycle 1 pre-dose on Day 2. Multiple-dose PK will be assessed from samples taken on Days 15 and 16 of Cycle 1.
Safety Issue:
Description:The concentration of AZD5153 and its co-former in blood will be determined. Tmax is the time required after administration for the drug to reach its peak plasma concentration.
Measure:Elimination half-lfe (t1/2).
Time Frame:Samples for single dose PK will be collected at prespecified time points on Day 1, Cycle 1 pre-dose on Day 2. Multiple-dose PK will be assessed from samples taken on Days 15 and 16 of Cycle 1.
Safety Issue:
Description:The concentration of AZD5153 and its co-former in blood will be determined. Elimination half-life (t1/2) is the time required for the concentration of the drug to reach half of its original value.
Measure:Volume of distribution (Vd).
Time Frame:Samples for single dose PK will be collected at prespecified time points on Day 1, Cycle 1 pre-dose on Day 2. Multiple-dose PK will be assessed from samples taken on Days 15 and 16 of Cycle 1.
Safety Issue:
Description:The concentration of AZD5153 and its co-former in blood will be determined. Volume of distribution (Vd) is the apparent volume in which a drug is distributed (i.e., the parameter relating drug concentration to drug amount in the body).
Measure:Clearance (CL).
Time Frame:Samples for single dose PK will be collected at prespecified time points on Day 1, Cycle 1 pre-dose on Day 2. Multiple-dose PK will be assessed from samples taken on Days 15 and 16 of Cycle 1.
Safety Issue:
Description:The concentration of AZD5153 and its co-former in blood will be determined. Clearance (CL) is the volume of plasma cleared of the drug per unit time.

Details

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

Trial Keywords

  • AZD5153
  • Olaparib
  • Malignant solid tumors
  • Lymphoma
  • Ovarian Cancer
  • BRD4

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