Clinical Trials /

AZD9150 Plus Durvalumab Alone or in Combination With Chemotherapy in Patients With Advanced, Solid Tumours and in Patients With Non-Small-Cell Lung Cancer

NCT03421353

Description:

This is a phase Ib/II, open-label multicentre study to assess the safety, tolerability, pharmacokinetics and preliminary anti-tumour activity of AZD9150 plus durvalumab alone or in combination with chemotherapy in patients with advanced, solid tumours and subsequently in patients with non-small-cell lung cancer (NSCLC).

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

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: AZD9150 Plus Durvalumab Alone or in Combination With Chemotherapy in Patients With Advanced, Solid Tumours and in Patients With Non-Small-Cell Lung Cancer
  • Official Title: A Phase Ib/II, Open-Label, Multicentre Study to Assess Safety, Tolerability, Pharmacokinetics and Preliminary Anti-tumour Activity of AZD9150 Plus Durvalumab Alone or in Combination With Chemotherapy in Patients With Advanced, Solid Tumours and Subsequently in Patients With Non-Small-Cell Lung Cancer

Clinical Trial IDs

  • ORG STUDY ID: D5660C00016
  • SECONDARY ID: REFMAL 558
  • NCT ID: NCT03421353

Conditions

  • Carcinoma, Non-small-cell Lung
  • Neoplasms
  • Carcinoma, Bronchogenic
  • Bronchial Neoplasms
  • Thoracic Neoplasms
  • Lung Neoplasms
  • Respiratory Tract Neoplasms

Interventions

DrugSynonymsArms
AZD9150A1: AZD9150 + Durvalumab
DurvalumabMEDI4736A1: AZD9150 + Durvalumab
CisplatinA2: AZD9150+ Durvalumab + Cisplatin + 5-FU
5-flourouracil5-FUA2: AZD9150+ Durvalumab + Cisplatin + 5-FU
CarboplatinA4:AZD9150+Durvalumab+Cisplatin/Carboplatin+Gemcitabine
GemcitabineA4:AZD9150+Durvalumab+Cisplatin/Carboplatin+Gemcitabine
Nab-paclitaxelA5:AZD9150+Durvalumab+Carboplatin+Nab-Paclitaxel

Purpose

This is a phase Ib/II, open-label multicentre study to assess the safety, tolerability, pharmacokinetics and preliminary anti-tumour activity of AZD9150 plus durvalumab alone or in combination with chemotherapy in patients with advanced, solid tumours and subsequently in patients with non-small-cell lung cancer (NSCLC).

Detailed Description

      This international, multicenter study will be conducted in three parts, designated A, B, and
      C.

      A complementary anti-tumour strategy will be used in this study with 2 immuno-therapeutics
      applied to restore effective anti-tumour immunity at 2 distinct stages: promoting the
      effector function of T-cell responses with an anti-PD-L1 mAb, durvalumab, while hindering
      immune escape in the tumour bed with AZD9150. In addition, chemotherapy will be added to this
      combination to investigate possible future enhancement of response. In preclinical models,
      conventional platinum-based chemotherapy has been shown to induce T-cell activation through
      the release of tumour-specific antigens during cancer cell death. The elimination of
      persistent tolerogenic tumour antigen environment via chemotherapy-induced debulking may also
      play a role in generating an effective immune response. In this setting, immunotherapy has
      the potential to mount an ongoing and dynamic immune response that can kill tumour cells for
      an extended time.

      Part A of the study will be conducted in 5 arms. The primary objective of Part A is to assess
      the safety, tolerability, and finding the maximum tolerated dose/recommended phase 2 dose
      (MTD/RP2D) of AZD9150 given every two weeks (Q2W) plus durvalumab given every four weeks
      (Q4W) in patients with advanced solid malignancies. In addition, the primary objective is to
      assess the safety, tolerability, and finding the maximum tolerated dose/recommended phase 2
      dose (MTD/RP2D) of AZD9150 plus durvalumab in combination with standard chemotherapy regimens
      in patients with advanced solid malignancies. Approximately 30 to 78 dose-limiting toxicity
      (DLT)-evaluable patients will be enrolled in this arm.

      Part B will be conducted in 2 arms and randomised 1:1. The primary objective of Part B is to
      evaluate the objective response rate (ORR) of durvalumab in combination with AZD9150 at
      different dosing schedules in patients with non-small-cell lung cancer (NSCLC). Approximately
      90 efficacy-evaluable patients will be enrolled in this arm.

      Part C will be one single arm. The primary objective of Part C is to evaluate the objective
      response rate (ORR) of durvalumab and AZD9150 with chemotherapy in 1st-line non-small-cell
      lung cancer (NSCLC) patients. Approximately 45 efficacy-evaluable patients will be enrolled
      in this arm.
    

Trial Arms

NameTypeDescriptionInterventions
A1: AZD9150 + DurvalumabExperimentalAZD9150 will be given every two weeks (Q2W) plus durvalumab given every four weeks (Q4W).
  • AZD9150
  • Durvalumab
A2: AZD9150+ Durvalumab + Cisplatin + 5-FUExperimentalAZD9150 will be given once weekly (QW) plus durvalumab every three weeks (Q3W) plus Cisplatin on Day 1 plus 5-flourouracil (5-FU) on Days 1 to 4. This regimen will be repeated every 3 weeks for up to 18 weeks. Post discontinuation of chemotherapy the regimen will be AZD9150 QW plus durvalumab Q4W.
  • AZD9150
  • Durvalumab
  • Cisplatin
  • 5-flourouracil
A3:AZD9150+Durvalumab+Cisplatin+5-FUExperimentalAZD9150 will be given every two weeks (Q2W) plus durvalumab given every three weeks (Q3W) plus cisplatin on Day 1 plus 5-flourouracil (5-FU) over Days 1 to 4. This regimen will be repeated every 3 weeks for up to 18 weeks.
  • AZD9150
  • Durvalumab
  • Cisplatin
  • 5-flourouracil
A4:AZD9150+Durvalumab+Cisplatin/Carboplatin+GemcitabineExperimentalAZD9150 will be given every two weeks (Q2W) plus durvalumab given every three weeks (Q3W) plus gemcitabine on Days 1 and 8. This regimen will be repeated every 3 weeks. In addition, the following will be added to the regimen: For cisplatin-eligible patients: cisplatin on Day 1 (every 3 weeks for up to 12-18 weeks); or For cisplatin ineligible patients: carboplatin on Day 1 and Day 8 (every 3 weeks for up to 12-18 weeks).
  • AZD9150
  • Durvalumab
  • Cisplatin
  • Carboplatin
  • Gemcitabine
A5:AZD9150+Durvalumab+Carboplatin+Nab-PaclitaxelExperimentalAZD9150 will be given every two weeks (Q2W) plus durvalumab every three weeks (Q3W) plus carboplatin on Day 1 plus nab-paclitaxel on Days 1, 8, and 15 (every 3 weeks for up to 12-18 weeks).
  • AZD9150
  • Durvalumab
  • Carboplatin
  • Nab-paclitaxel
B1: AZD9150 + DurvalumabExperimentalAZD9150 will be given once weekly (QW) plus durvalumab every four weeks (Q4W). 1:1 Randomization
  • AZD9150
  • Durvalumab
B2: AZD9150 + DurvalumabExperimentalAZD9150 will be given every two weeks (Q2W) plus durvalumab every four weeks (Q4W). 1:1 Randomization
  • AZD9150
  • Durvalumab
C1:AZD9150+Durvalumab+Carboplatin+Nab-PaclitaxelExperimentalAZD9150 will be given every two weeks (Q2W) plus durvalumab every three weeks (Q3W) plus standard of care (SOC) chemotherapy (nab-paclitaxel plus carboplatin Q3W) for 12-18 weeks followed by AZD9150 Q2W plus durvalumab Q4W.
  • AZD9150
  • Durvalumab
  • Carboplatin
  • Nab-paclitaxel

Eligibility Criteria

        Inclusion Criteria:

          -  An Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1 and a
             minimum life expectancy of 12 weeks

          -  Part A of the study will include patients that have histological confirmation of a
             solid malignancy (other than HCC) that is refractory to standard therapy or for which
             no standard of care regimen currently exists.

          -  Parts B of the study will include patients with histological or cytological
             confirmation diagnosis of locally advanced or metastatic Stage IV NSCLC.

          -  Part C of the study will include patients with histological or cytological
             confirmation diagnosis of locally advanced or metastatic Stage IV 1st-line NSCLC (for
             which the patient has not received therapy).

          -  Willing to undergo mandatory biopsy at screening and on treatment. Part A only: the
             first 3 subjects in each cohort are exempt from this requirement.

          -  At least one lesion, not previously irradiated, that can be accurately measured at
             baseline as ≥10 mm in the longest diameter (except lymph nodes that must have short
             axis ≥15 mm) with computerised tomography (CT) or magnetic resonance imaging (MRI)
             that is suitable for accurate repeated measurements.

          -  Females should be using adequate contraceptive measures, should 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-child-bearing potential by fulfilling one of
             the following criteria at screening:

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

          -  Women under 50 years old would be considered postmenopausal if they have been
             amenorrheic for 12 months or more following cessation of exogenous hormonal treatments
             and with luteinizing hormone and follicle-stimulating hormone levels in the
             post-menopausal range for the institution

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

          -  Male patients must be surgically sterile or using an acceptable method of
             contraception (defined as barrier methods in conjunction with spermicides) for the
             duration of the study (from the time they sign consent) and for 20 weeks after the
             last dose of study treatments

          -  For inclusion in the optional PGx research, patients must provide informed consent for
             the genetic sampling and analyses.

        Exclusion Criteria:

          -  Involvement in the planning and/or conduct of the study (applies to AstraZeneca and/or
             Sarah Cannon Development Innovations staff and/or staff at the study site).

          -  Previous enrolment in the present study.

          -  For Parts B and C, patients who received previous anti- PD-1, anti-PD-(L)1 treatment

          -  Brain metastases or spinal cord compression unless asymptomatic and not requiring
             steroids for at least 14 days prior to start of study treatment

          -  Active interstitial lung disease (ILD)/pneumonitis or a prior history of
             ILD/pneumonitis requiring treatment with steroids.

          -  For Part B and Part C, patients with tumors bearing genetic abnormalities for which
             health authority-approved targeted therapies exist will not be enrolled; e.g, patients
             with mutations including but not limited to ROS rearrangements, BRAF V600E, EGFR
             mutations or ALK translocation patients will not be considered eligible

          -  For part B and part C, Presence of other active invasive cancers other than NSCLC or
             history of treatment for invasive cancer other than NSCLC in the past 3 years.

        Exceptions are:

          -  Previously treated in situ carcinoma (i.e., noninvasive)

          -  Cervical carcinoma Stage 1B or less

          -  Noninvasive basal cell and squamous cell skin carcinoma

          -  Radically treated prostate cancer (prostatectomy or radiotherapy) with normal
             prostate-specific antigen, and not requiring ongoing antiandrogen hormonal therapy.

          -  Patients receiving any concurrent chemotherapy, radiotherapy, immunotherapy, or
             biologic, or hormonal therapy for cancer (concurrent use of hormones for
             noncancer-related conditions [e.g., insulin for diabetes and hormone replacement
             therapy] is acceptable)

        Patients must have completed any previous cancer-related treatments before enrolment. The
        following intervals between the end of the prior treatment and first dose of study drug
        must be observed:

          -  Port-a-cath placement: no waiting is required

          -  Minor surgical procedures (as defined by the Investigator): 7 postoperative days

          -  Major surgery (as defined by the Investigator): ≥4 weeks

          -  Radiotherapy: ≥4 weeks (patients who receive palliative radiation for nontarget tumour
             lesions need not be subjected to this washout period and can be enrolled immediately)

          -  Chemotherapy: within 21 days or 5 half-lives (whichever is longer) from enrolment

          -  Immunotherapy and/or investigational anticancer therapy with agents including mAbs :
             ≥4 weeks

          -  Use of intranasal and inhaled corticosteroids or systemic corticosteroids at
             physiologic doses not to exceed 10 mg/day of prednisone or equivalent is permitted.

          -  Part A patients who have received more than 3 prior cytoreductive chemotherapy
             regimens.

          -  Has active or prior documented autoimmune disease within the past 2 years with the
             exceptions of vitiligo, Grave's disease, and/or psoriasis not requiring systemic
             treatment

          -  Has active or prior documented inflammatory bowel disease (e.g., Crohn's disease,
             ulcerative colitis)

          -  Has a history of primary immunodeficiency

          -  Has undergone an organ transplant that requires use of immunosuppressive treatment

          -  Any of the following cardiac criteria:

          -  Mean resting corrected QT interval (QTc) calculated using Fridericia's formula (QTcF)
             of >450 msec for males and >470 msec for females obtained from 3 electrocardiograms
             (ECGs) taken over 5 minutes

          -  Any clinically important abnormalities in rhythm, conduction or morphology of a
             resting ECG, e.g., complete left bundle branch block, third degree heart block, that
             in the opinion of the Investigator render the patient unsuitable for participation in
             the study

          -  Any factors that increase the risk of QTc prolongation or risk of arrhythmic events
             such as heart failure, hypokalaemia, 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

          -  Inadequate organ and marrow function as demonstrated by any of the following
             laboratory values. Transfusions intended to elevate any parameters below solely for
             the intent of meeting study eligibility are not permitted.

          -  Leukocytes <3.0 x 109/L

          -  Absolute neutrophil count <1.5 x 109/L

          -  Platelet count <100 x 109/L

          -  Haemoglobin <90 g/L

          -  Alanine aminotransferase (ALT) or aspartate aminotransferase (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 if no liver metastases or 3 times ULN in the presence
             of liver metastases or documented Gilbert's Syndrome (unconjugated
             hyperbilirubinaemia)

          -  Creatinine outside normal limits OR, if creatinine outside normal limits, a creatinine
             clearance <60 mL/min (measured by 24-hour urine collection or calculated by Cockcroft
             and Gault equation (Cockcroft and Gault 1976).

          -  Has a history of allergic reactions attributed to the study treatments (AZD9150 or
             durvalumab), assigned chemotherapy agents, their compounds, or agents of similar
             chemical or biologic composition (e.g., antibody therapeutics)

          -  Suffers from a comorbidity that in the opinion of the Investigator renders the patient
             unsuitable for participation in the study. Such comorbidity may include, but is not
             limited to, uncontrolled intercurrent illness such as active infection, severe active
             peptic ulcer disease or gastritis, myocardial infarction within 6 months before entry,
             congestive heart failure, symptomatic congestive heart failure, active cardiomyopathy,
             unstable angina pectoris, cardiac arrhythmia, uncontrolled hypertension, or
             psychiatric illness/social situations that would limit compliance with study
             requirements.

          -  As judged by the Investigator, has any evidence of severe or uncontrolled diseases
             such as active bleeding diatheses, or has an active viral infection of human
             immunodeficiency virus (HIV), human papilloma virus (HPV), hepatitis B virus (HBV),
             and/or hepatitis C virus (HCV)

          -  Has a known history of tuberculosis

          -  Has received a live attenuated vaccine within 28 days before the first dose of study
             drug

          -  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.
      
Maximum Eligible Age:130 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Part A: Incidence of treatment-emergent adverse events (TEAEs)
Time Frame:Through study completion (an average of 6 months)
Safety Issue:
Description:The incidence of TEAEs will be assessed for each treatment arm in Part A of the study.

Secondary Outcome Measures

Measure:Part A: Peak plasma concentration (Cmax) of AZD9150 and durvalumab.
Time Frame:Samples will be collected predose, and 0.5 hours, approximately 1 hour (end of AZD9150 infusion), and 2, 4, 6, and 48 hours post dose on pre-specified dosing days up to 9 weeks.
Safety Issue:
Description:
Measure:Part A: Area under the plasma concentration versus time curve (AUC) of AZD9150 and durvalumab.
Time Frame:Samples will be collected predose, and 0.5 hours, approximately 1 hour (end of AZD9150 infusion), and 2, 4, 6, and 48 hours post dose on pre-specified dosing days up to 9 weeks.
Safety Issue:
Description:
Measure:Parts B1 and B2: Peak plasma concentration (Cmax) of AZD9150
Time Frame:Samples will be collected predose, and 0.5 hours, approximately 1 hour (end of AZD9150 infusion), and 2, 4, 6, and 48 hours post dose on pre-specified dosing days up to 9 weeks.
Safety Issue:
Description:
Measure:Parts B1 and B2: Area under the plasma concentration versus time curve (AUC) of AZD9150
Time Frame:Samples will be collected predose and at the end of infusion of AZD9150 (approximately 1 hour) post dose on pre-specified dosing days up to 9 weeks.
Safety Issue:
Description:
Measure:Parts B1 and B2: Peak plasma concentration (Cmax) of durvalumab.
Time Frame:Samples will be collected predose and at the end of infusion of durvalumab. Durvalumab infusion will be over approx. 1 hr and will be the 2nd infusion (after AZD9150) on pre-specified dosing days up to 13 weeks.
Safety Issue:
Description:
Measure:Parts B1 and B2: Area under the plasma concentration versus time curve (AUC) of durvalumab.
Time Frame:Samples will be collected predose and at the end of infusion of durvalumab. Durvalumab infusion will be over approx. 1 hr and will be the 2nd infusion (after AZD9150) on pre-specified dosing days up to 13 weeks.
Safety Issue:
Description:
Measure:Part C: Peak plasma concentration (Cmax) of AZD9150
Time Frame:Samples will be collected predose and approximately 1 hour (at the end of infusion of AZD9150) post dose on pre-specified dosing days up to 9 weeks.
Safety Issue:
Description:
Measure:Part C: Area under the plasma concentration versus time curve (AUC) of AZD9150
Time Frame:Samples will be collected predose and approximately 1 hour (at the end of infusion of AZD9150) post dose on pre-specified dosing days up to 9 weeks.
Safety Issue:
Description:
Measure:Part C: Peak plasma concentration (Cmax) of durvalumab.
Time Frame:Samples will be collected predose and at the end of infusion of durvalumab. Durvalumab infusion will be over approx. 1 hr and will be the 2nd infusion (after AZD9150) on pre-specified dosing days up to 13 weeks.
Safety Issue:
Description:
Measure:Part C: Area under the plasma concentration versus time curve (AUC) of durvalumab.
Time Frame:Samples will be collected predose and at the end of infusion of durvalumab. Durvalumab infusion will be over approx. 1 hr and will be the 2nd infusion (after AZD9150) on pre-specified dosing days up to 13 weeks.
Safety Issue:
Description:
Measure:Parts A, B, and C: AZD9150 anti-drug antibodies
Time Frame:Blood samples for AZD9150 anti-drug antibodies (ADAs) will be collected predose on prespecified dosing days up to 9 weeks.
Safety Issue:
Description:
Measure:Parts A, B, and C: Durvalumab anti-drug antibodies
Time Frame:Blood samples for durvalumab anti-drug antibodies (ADAs) will be collected predose on prespecified dosing days up to 13 weeks.
Safety Issue:
Description:
Measure:Parts A, B, and C: Baseline tumour PD-L1 expression
Time Frame:Pre-dose
Safety Issue:
Description:Tumour sample may be from a biopsy taken for diagnosis of NSCLC (archival) or one taken at screening.
Measure:Parts A, B, and C: Disease control rate (DCR)
Time Frame:12 weeks
Safety Issue:
Description:Disease Control Rate (DCR) is defined (RECIST v1.1) as the percentage of patients who have achieved complete response, partial response or stable disease.
Measure:Parts A, B, and C: Duration of Overall Response (DoR)
Time Frame:From the date of documented complete response or partial response, whichever comes first, until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 12 months
Safety Issue:
Description:The duration of overall response is measured from the time measurement criteria are met for Complete Response (CR) or Partial Response (PR) (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented.
Measure:Parts A, B, and C: Progression-free Survival (PFS)
Time Frame:From the beginning of treatment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 12 months
Safety Issue:
Description:Progression-free survival (PFS) is defined as the time from the beginning of treatment to disease progression or death from any cause.
Measure:Parts A, B, and C: Overall Survival (OS)
Time Frame:From the beginning of treatment until the date of death from any cause, assessed up to 12 months
Safety Issue:
Description:Overall survival (OS) is defined as the time from the beginning of treatment to death from any cause.
Measure:Parts A, B, and C: Proportion of patients alive at 12 months
Time Frame:12 months
Safety Issue:
Description:Defined as the total number of patients alive 12 months after start of treatment divided by the number of patients that started treatment for each arm of the study.
Measure:Parts A, B, and C: STAT3 protein in tumour biopsies
Time Frame:Predose and 3 weeks after start of treatment
Safety Issue:
Description:Baseline and on-treatment biopsies will be used to measure STAT3 expression levels by immunohistochemistry.
Measure:Part B: Incidence of treatment-emergent adverse events (TEAEs)
Time Frame:Through study completion (an average of 6 months)
Safety Issue:
Description:The incidence of TEAEs will be assessed for each treatment arm in Part B of the study.
Measure:Part C: Incidence of treatment-emergent adverse events (TEAEs)
Time Frame:Through study completion (an average of 6 months)
Safety Issue:
Description:The incidence of TEAEs will be assessed for each treatment arm in Part C of the study.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:AstraZeneca

Trial Keywords

  • AZD9150
  • Durvalumab
  • NSCLC
  • Non-small-cell lung cancer
  • Advanced solid malignancies

Last Updated

January 29, 2018