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Safety And Efficacy Study Of Avelumab Plus Chemotherapy With Or Without Other Anti-Cancer Immunotherapy Agents In Patients With Advanced Malignancies

NCT03317496

Description:

This is a Phase 1b/2, open label, multicenter, safety and clinical activity study of avelumab in combination with chemotherapy as first-line treatment of adult patients with locally advanced or metastatic solid tumors. Initially, avelumab will be evaluated in combination with pemetrexed and carboplatin in patients with advanced non-squamous non-small cell lung cancer (NSCLC) (Cohort A1) and in combination with gemcitabine and cisplatin in patients with cisplatin-eligible urothelial (bladder) cancer (UC) (Cohort A2). As more information is learned about other anti-cancer immunotherapy agents, in future portions of the study, avelumab may be combined with chemotherapy and other anti-cancer immunotherapy agents in patients with these same or different tumor types.

Related Conditions:
  • Bladder Urothelial Carcinoma
  • Infiltrating Renal Pelvis and Ureter Urothelial Carcinoma
  • Non-Small Cell Lung Carcinoma
  • Renal Pelvis Urothelial Carcinoma
  • Ureter Urothelial Carcinoma
  • Urethral Urothelial Carcinoma
  • Urothelial Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Safety And Efficacy Study Of Avelumab Plus Chemotherapy With Or Without Other Anti-Cancer Immunotherapy Agents In Patients With Advanced Malignancies
  • Official Title: A MULTICENTER, OPEN-LABEL, PHASE 1B/2 STUDY TO EVALUATE SAFETY AND EFFICACY OF AVELUMAB (MSB0010718C) IN COMBINATION WITH CHEMOTHERAPY WITH OR WITHOUT OTHER ANTI-CANCER IMMUNOTHERAPIES AS FIRST-LINE TREATMENT IN PATIENTS WITH ADVANCED MALIGNANCIES

Clinical Trial IDs

  • ORG STUDY ID: B9991023
  • SECONDARY ID: B9991023
  • SECONDARY ID: 2017-001741-27
  • SECONDARY ID: JAVELIN CHEMOTHERAPY MEDLEY
  • NCT ID: NCT03317496

Conditions

  • Non-small Cell Lung Cancer
  • Urothelial Cancer

Interventions

DrugSynonymsArms
Avelumab 800 mg in combination with pemetrexed / carboplatinGroup A Cohort A1
Avelumab 800 mg in combination with gemcitabine / cisplatin.Group A Cohort A2
Avelumab 1200 mg in combination with pemetrexed/carboplatinGroup A Cohort A3
Avelumab 1200 mg in combination with gemcitabine/cisplatinGroup A Cohort A4

Purpose

This is a Phase 1b/2, open label, multicenter, safety and clinical activity study of avelumab in combination with chemotherapy as first-line treatment of adult patients with locally advanced or metastatic solid tumors. Initially, avelumab will be evaluated in combination with pemetrexed and carboplatin in patients with advanced non-squamous non-small cell lung cancer (NSCLC) (Cohort A1) and in combination with gemcitabine and cisplatin in patients with cisplatin-eligible urothelial (bladder) cancer (UC) (Cohort A2). As more information is learned about other anti-cancer immunotherapy agents, in future portions of the study, avelumab may be combined with chemotherapy and other anti-cancer immunotherapy agents in patients with these same or different tumor types.

Detailed Description

      This is a Phase 1b/2, open label, multicenter, safety, clinical activity, pharmacokinetic
      (PK), and pharmacodynamics (PD) study of avelumab in combination with chemotherapy with or
      without other anti-cancer immunotherapies, as first-line treatment of adult patients with
      locally advanced or metastatic solid tumors. Initially, avelumab will be evaluated in
      combination with pemetrexed and carboplatin in patients with advanced non-squamous non-small
      cell lung cancer (NSCLC) (Cohort A1) and with gemcitabine and cisplatin in patients with
      cisplatin-eligible urothelial cancer (UC) (Cohort A2).

      Given the growing preclinical and clinical indications that combinations of anti-cancer
      immunotherapies potentially improve patient outcomes compared to results seen with single
      agents, in portions of the study to be added in the future, avelumab will be evaluated in
      combination with both standard-of-care chemotherapy and other anti-cancer immunotherapies in
      patients with advanced malignancies. Each cohort in the study will consist of a Phase 1b
      lead-in portion to evaluate safety and a Phase 2 cohort expansion to evaluate safety and
      efficacy.

      In the Phase 1b safety lead-in portion, up to 12 patients will be enrolled into each cohort
      and evaluated for dose-limiting toxicities (DLT) during the first 2 cycles of treatment. If
      investigational products administration in a cohort is deemed safe in the Phase 1b lead-in,
      enrollment may be expanded into the Phase 2 cohort expansion. Up to approximately 40 patients
      in each cohort (including those enrolled in the Phase 1b lead-in and those enrolled in the
      Phase 2 cohort expansion) will be enrolled and treated with avelumab plus chemotherapy in the
      initial portion of the study and, in future portions of the study, with avelumab plus
      chemotherapy with or without other anti-cancer immunotherapies.

      In the Phase 1b lead-in portions of NSCLC Cohort A1 and UC Cohort A2, avelumab is dosed at
      800 mg fixed dose every 3 weeks. Under Protocol Amendment 4, avelumab is dosed at 1200 mg
      fixed dose every 3 weeks in the Phase 1b lead-in portions of NSCLC Cohort A3 and in UC Cohort
      A4, in combination with the same standard-of-care chemotherapy doublets used in Cohort A1 and
      Cohort A2, respectively. For each tumor type, the study treatment combination with the
      highest avelumab dose determined to be safe may be advanced into Phase 2 cohort expansion.
    

Trial Arms

NameTypeDescriptionInterventions
Group A Cohort A1ExperimentalNon-squamous non-small cell lung cancer (NSCLC) patients treated with 800 mg avelumab plus pemetrexed/carboplatin
  • Avelumab 800 mg in combination with pemetrexed / carboplatin
Group A Cohort A2ExperimentalCisplatin-eligible urothelial cancer (UC)patients treated with 800 mg avelumab plus gemcitabine/cisplatin
  • Avelumab 800 mg in combination with gemcitabine / cisplatin.
Group A Cohort A3ExperimentalNon-squamous non-small cell lung cancer (NSCLC) patients treated with 1200 mg avelumab plus pemetrexed/carboplatin
  • Avelumab 1200 mg in combination with pemetrexed/carboplatin
Group A Cohort A4ExperimentalCisplatin-eligible urothelial cancer (UC) patients treated with 1200 mg avelumab plus gemcitabine/cisplatin
  • Avelumab 1200 mg in combination with gemcitabine/cisplatin

Eligibility Criteria

        Inclusion Criteria:

          1. Histological diagnosis of locally advanced (primary or recurrent) or metastatic solid
             tumor that is not amenable for treatment with curative intent as follows:

               -  For all groups:

               -  Measurable disease by RECIST v1.1 with at least 1 measurable lesion, and
                  availability of tumor specimen 18 months or less old.

               -  No prior systemic treatment for unresectable locally advanced or metastatic
                  disease for the tumor type under study. If prior systemic chemotherapy treatment
                  was given in the adjuvant or neo-adjuvant setting or as part of radiotherapy
                  chemotherapy treatment, disease-free interval after stop of systemic treatment
                  must be more than 6 months for non-squamous NSCLC and more than 12 months for UC;

               -  Cohort A1 and Cohort A3: Non-squamous NSCLC, with no activating EGFR mutations,
                  ALK or ROS1 translocations/rearrangements. If monotherapy pembrolizumab is
                  available as a standard of care treatment option, patients must have a tumor
                  proportion score (TPS) <50% for PD L1 (via the 22C3 pharmDx or the Ventana
                  (SP263) PD L1 IHC assay).

               -  Cohort A2 and Cohort A4: Transitional cell carcinoma of the urothelium including
                  the bladder, urethra, renal pelvis, and ureter.

          2. ECOG performance status 0 or 1

          3. Estimated life expectancy of at least 90 days

          4. Adequate bone marrow, renal, and liver function

          5. Negative serum pregnancy test at screening

          6. Signed and dated informed consent

        Exclusion Criteria:

          1. Prior immunotherapy with any antibody or drug specifically targeting T cell
             co-stimulation or immune checkpoint pathways.

          2. Patients with known symptomatic central nervous system metastases requiring steroids.

          3. Diagnosis of other malignancy within 2 years prior to enrollment except adequately
             treated basal cell or squamous cell skin cancer, or carcinoma in situ of the bladder,
             breast, or cervix, or low grade (Gleason ≤6) prostate cancer

          4. Use of immunosuppressive medication at the time of enrollment

          5. Active or prior autoimmune disease that might deteriorate when receiving an
             immuno-stimulatory agent.

          6. Prior organ transplantation including allogenic stem cell transplantation

          7. Active infection requiring systemic therapy

          8. Known history of HIV or AIDS

          9. Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening

         10. Administration of live vaccine within 4 weeks prior to study entry

         11. Known prior severe hypersensitivity to the investigational products or any component
             in their formulations,

         12. Known prior severe hypersensitivity to platinum-related compounds for all cohorts, to
             pemetrexed for patients enrolled in Cohort A1 and Cohort A3, and to gemcitabine for
             patients enrolled in Cohort A2 and Cohort A4

         13. Persisting toxicity related to prior therapy (NCI CTCAE v4.03 Grade > 1)

         14. Known history of colitis, inflammatory bowel disease, pneumonitis, pulmonary fibrosis.

         15. Ongoing cardiac dysrhythmias of NCI CTCAE v4.03 Grade 2 or prolongation of the QTcF
             interval to >480 msec.

         16. Clinically significant (ie, active) cardiovascular disease: cerebral vascular
             accident/stroke (<6 months prior to enrollment), myocardial infarction (< 6 months
             prior to enrollment), unstable angina, congestive heart failure, or serious cardiac
             arrhythmia requiring medication.

         17. Major surgery ≤28 days or major radiation therapy ≤14 days prior to enrollment.

         18. Participation in other studies involving investigational drug(s) within 28 days prior
             to study entry.

         19. Concurrent treatment with a prohibited medication.

         20. Other acute or chronic medical or psychiatric condition

         21. Pregnant female patients; breastfeeding female patients; fertile male patients and
             female patients of childbearing potential who are unwilling or unable to use at least
             1 highly effective method of contraception as outlined in this protocol for the
             duration of the study and for at least 90 days after the last dose of chemotherapy
             (for male and female patients) or at least 30 days after the last dose of avelumab
             (for female patients), whichever is longer.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Phase 1b lead-in: Number of patients with dose-limiting toxicities in first 2 cycles
Time Frame:First 6 weeks of treatment
Safety Issue:
Description:Dose-limiting toxicity rate in first 6 (or 12) patients enrolled in safety Phase 1b lead-in of each cohort

Secondary Outcome Measures

Measure:Progression-Free Survival (PFS)
Time Frame:Baseline up to approximately 24 months
Safety Issue:
Description:Progression-Free Survival (PFS) is defined as the time from the first dose of study treatment to the date of disease progression by RECIST v1.1 or death due to any cause, whichever occurs first.
Measure:Duration of Response (DR)
Time Frame:Baseline up to approximately 24 months
Safety Issue:
Description:Duration of Response (DR) is defined for patients with confirmed objective response (CR or PR) as the time from the first documentation of objective tumor response to the first documentation of objective tumor progression or to death due to any cause, whichever occurs first.
Measure:Time to Tumor Response (TTR)
Time Frame:Baseline up to approximately 24 months
Safety Issue:
Description:Time to Tumor Response (TTR) is defined for patients with confirmed objective response (CR or PR) as the time from the first dose of study treatment to the first documentation of objective tumor response.
Measure:Overall Survival (OS)
Time Frame:Baseline up to approximately 24 months
Safety Issue:
Description:Overall Survival (OS) is defined as the time from the first dose of study treatment to the date of death.
Measure:Plasma concentrations of cisplatin
Time Frame:Day 1 and Day 8 of Cycle 2
Safety Issue:
Description:Pharmacokinetic assessment of cisplatin
Measure:Plasma concentrations of gemcitabine
Time Frame:Day 1 of Cycle 2
Safety Issue:
Description:Pharmacokinetic assessment of gemcitabine
Measure:Plasma concentrations of pemetrexed
Time Frame:Day 1 and Day 8 of Cycle 2
Safety Issue:
Description:Pharmacokinetic assessment of pemetrexed
Measure:Plasma concentrations of carboplatin
Time Frame:Day 1 and Day 8 of Cycle 2
Safety Issue:
Description:Pharmacokinetic assessment of carboplatin
Measure:Serum concentrations of avelumab
Time Frame:Pre-dose and 1 hour post-dose on Day 1 of Cycles 1, 2, 3, 6, 10, and 14, and during the Day 15 visit of Cycles 1, 2, and 3
Safety Issue:
Description:Pharmacokinetic assessment of avelumab
Measure:Anti-Drug Antibody (ADA) levels of avelumab
Time Frame:Pre-dose on Day 1 of Cycles 1, 2, 3, 6, 10, and 14, and at End of Treatment
Safety Issue:
Description:Immunogenicity assessment of avelumab
Measure:Mutational load within baseline tumor tissue
Time Frame:Baseline
Safety Issue:
Description:Assessment of the number of mutations present per megabase of DNA within the tumor
Measure:PD-L1 expression in baseline and on-treatment tumor tissue
Time Frame:Baseline and Cycle 2 Day 8 (+/- 7 days)
Safety Issue:
Description:Assessment of PD-L1 expression in tumor tissue obtained prior to treatment with study drug and while on study treatment

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Pfizer

Trial Keywords

  • Avelumab, immunotherapy, PD-L1 inhibitor, non-small cell lung cancer (NSCLC), urothelial cancer (UC), carboplatin, pemetrexed, gemcitabine, cisplatin

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