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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

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ClinicalTrials.gov Identifier: NCT03317496
Recruitment Status : Recruiting
First Posted : October 23, 2017
Last Update Posted : July 9, 2019
Sponsor:
Information provided by (Responsible Party):
Pfizer

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Non-small Cell Lung Cancer Urothelial Cancer Drug: Avelumab 800 mg in combination with pemetrexed / carboplatin Drug: Avelumab 800 mg in combination with gemcitabine / cisplatin. Drug: Avelumab 1200 mg in combination with pemetrexed/carboplatin Drug: Avelumab 1200 mg in combination with gemcitabine/cisplatin Phase 2

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 80 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : December 21, 2017
Estimated Primary Completion Date : September 4, 2020
Estimated Study Completion Date : September 4, 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Group A Cohort A1
Non-squamous non-small cell lung cancer (NSCLC) patients treated with 800 mg avelumab plus pemetrexed/carboplatin
Drug: Avelumab 800 mg in combination with pemetrexed / carboplatin
Avelumab Pemetrexed Carboplatin

Experimental: Group A Cohort A2
Cisplatin-eligible urothelial cancer (UC)patients treated with 800 mg avelumab plus gemcitabine/cisplatin
Drug: Avelumab 800 mg in combination with gemcitabine / cisplatin.
Avelumab Gemcitabine Cisplatin

Experimental: Group A Cohort A3
Non-squamous non-small cell lung cancer (NSCLC) patients treated with 1200 mg avelumab plus pemetrexed/carboplatin
Drug: Avelumab 1200 mg in combination with pemetrexed/carboplatin
Avelumab Pemetrexed Carboplatin

Experimental: Group A Cohort A4
Cisplatin-eligible urothelial cancer (UC) patients treated with 1200 mg avelumab plus gemcitabine/cisplatin
Drug: Avelumab 1200 mg in combination with gemcitabine/cisplatin
Avelumab Gemcitabine Cisplatin




Primary Outcome Measures :
  1. Phase 1b lead-in: Number of patients with dose-limiting toxicities in first 2 cycles [ Time Frame: First 6 weeks of treatment ]
    Dose-limiting toxicity rate in first 6 (or 12) patients enrolled in safety Phase 1b lead-in of each cohort

  2. Confirmed objective response (OR) [ Time Frame: Baseline up to approximately 24 months ]
    For each cohort, number of patients in the Phase 1b lead-in and Phase 2 cohort expansion with objective response (confirmed complete or partial response) according to RECIST Version 1.1 from the first dose of study treatment until disease progression or death due to any cause.


Secondary Outcome Measures :
  1. Progression-Free Survival (PFS) [ Time Frame: Baseline up to approximately 24 months ]
    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.

  2. Duration of Response (DR) [ Time Frame: Baseline up to approximately 24 months ]
    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.

  3. Time to Tumor Response (TTR) [ Time Frame: Baseline up to approximately 24 months ]
    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.

  4. Overall Survival (OS) [ Time Frame: Baseline up to approximately 24 months ]
    Overall Survival (OS) is defined as the time from the first dose of study treatment to the date of death.

  5. Plasma concentrations of cisplatin [ Time Frame: Day 1 and Day 8 of Cycle 2 ]
    Pharmacokinetic assessment of cisplatin

  6. Plasma concentrations of gemcitabine [ Time Frame: Day 1 of Cycle 2 ]
    Pharmacokinetic assessment of gemcitabine

  7. Plasma concentrations of pemetrexed [ Time Frame: Day 1 and Day 8 of Cycle 2 ]
    Pharmacokinetic assessment of pemetrexed

  8. Plasma concentrations of carboplatin [ Time Frame: Day 1 and Day 8 of Cycle 2 ]
    Pharmacokinetic assessment of carboplatin

  9. 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 ]
    Pharmacokinetic assessment of avelumab

  10. 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 ]
    Immunogenicity assessment of avelumab

  11. Mutational load within baseline tumor tissue [ Time Frame: Baseline ]
    Assessment of the number of mutations present per megabase of DNA within the tumor

  12. PD-L1 expression in baseline and on-treatment tumor tissue [ Time Frame: Baseline and Cycle 2 Day 8 (+/- 7 days) ]
    Assessment of PD-L1 expression in tumor tissue obtained prior to treatment with study drug and while on study treatment



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03317496


Contacts
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Contact: Pfizer CT.gov Call Center 1-800-718-1021 ClinicalTrials.gov_Inquiries@pfizer.com

  Show 71 Study Locations
Sponsors and Collaborators
Pfizer
Investigators
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Study Director: Pfizer CT.gov Call Center Pfizer

Additional Information:
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Responsible Party: Pfizer
ClinicalTrials.gov Identifier: NCT03317496     History of Changes
Other Study ID Numbers: B9991023
B9991023 ( Other Identifier: Pfizer )
2017-001741-27 ( EudraCT Number )
JAVELIN CHEMOTHERAPY MEDLEY ( Other Identifier: Alias Study Number )
First Posted: October 23, 2017    Key Record Dates
Last Update Posted: July 9, 2019
Last Verified: July 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.
URL: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Pfizer:
Avelumab, immunotherapy, PD-L1 inhibitor, non-small cell lung cancer (NSCLC), urothelial cancer (UC), carboplatin, pemetrexed, gemcitabine, cisplatin

Additional relevant MeSH terms:
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Carcinoma, Non-Small-Cell Lung
Carcinoma, Bronchogenic
Bronchial Neoplasms
Lung Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Cisplatin
Gemcitabine
Carboplatin
Pemetrexed
Antibodies, Monoclonal
Antineoplastic Agents
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Folic Acid Antagonists
Nucleic Acid Synthesis Inhibitors