Clinical trial NCT03317496: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Non-small Cell Lung Cancer
Urothelial Cancer
Keywords: Avelumab, immunotherapy, PD-L1 inhibitor, non-small cell lung cancer (NSCLC), urothelial cancer (UC), carboplatin, pemetrexed, gemcitabine, cisplatin
Lead sponsor: Pfizer
Sponsor class: INDUSTRY
First posted: 2017-10-23
Enrollment: 67
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

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.

Primary outcomes:
measure: Phase 1b Lead-in: Number of Participants With Dose-Limiting Toxicities (DLT)
timeFrame: Day 1 up to Week 6 (first 2 treatment cycles; 1 cycle = 21 days)
measure: Percentage of Participants With Confirmed Objective Response (OR) as Per Response Evaluation Criteria in Solid Tumors (RECIST) Version (v) 1.1 by Investigator Assessment
timeFrame: From start of the treatment until disease progression or death due to any cause, whichever occurred first (maximum up to 3.5 years approximately)
Secondary outcomes:
measure: Serum Concentration of Avelumab
timeFrame: Pre-dose, 1 hour post-dose on Day 1 of Cycle 1, 2, 3, 6, 10, 14; 336 hours post-dose on Day 15 of Cycle 1, 2, 3 (each cycle of 21 days)
measure: Absolute Value of Tumor Mutational Burden (TMB) in Tumor Tissue
timeFrame: Pre-dose on Day 1 of Cycle 1
measure: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs
timeFrame: From start of the treatment up to 30 days after last dose or start of new anticancer therapy minus 1 day, whichever occurred first (maximum up to 5 years approximately)
measure: Number of Participants With Treatment Related TEAEs
timeFrame: From start of the treatment up to 30 days after last dose or start of new anticancer therapy minus 1 day, whichever occurred first (maximum up to 5 years approximately)
measure: Number of Participants With Grade 3 or Higher TEAEs Based on National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) v 4.03
timeFrame: From start of the treatment up to 30 days after last dose or start of new anticancer therapy minus 1 day, whichever occurred first (maximum up to 5 years approximately)
measure: Number of Participants With Grade 3 or Higher Laboratory Abnormalities by CTCAE Grade
timeFrame: From screening up to 90 days after last dose of study drug (maximum up to 5 years approximately)
measure: Number of Participants With Positive Anti-Drug Antibody (ADA) and Neutralizing Antibodies for Avelumab
timeFrame: From first dose of study drug up to last dose of study drug (maximum up to 5 years approximately)
measure: Progression Free Survival (PFS) as Per RECIST v 1.1 by Investigator Assessment
timeFrame: From start of treatment until disease progression or death due to any cause, whichever occurred first (maximum up to 5 years approximately)
measure: Overall Survival (OS)
timeFrame: From first dose of study treatment until death due to any cause (maximum up to 5 years approximately)
measure: Duration of Response (DOR) as Per RECIST v 1.1 by Investigator Assessment
timeFrame: From date of first documented response to date of first documented PD or death due to any cause, whichever occurred first (maximum up to 5 years approximately)
measure: Time-to-Tumor Response (TTR) as Per RECIST v 1.1 by Investigator Assessment
timeFrame: From first dose of study treatment until first documentation of CR or PR (maximum up to 5 years approximately)
measure: Number of Participants With Programmed Death-Ligand 1 (PD-L1) Expression
timeFrame: Baseline and Cycle 2 Day 8 (each cycle of 21 days)
Other outcomes:
Locations:
city: Tucson
country: United States
facility: University of Arizona Cancer Center - North Campus
state: Arizona
city: Tucson
country: United States
facility: Banner-University Medical Center Tucson
state: Arizona
city: Bronx
country: United States
facility: Montefiore Medical Center - Einstein Center for Cancer Care
state: New York
city: Bronx
country: United States
facility: Montefiore Medical Center - Moses Division
state: New York
city: Stony Brook
country: United States
facility: Stony Brook Cancer Center
state: New York
city: Stony Brook
country: United States
facility: Stony Brook University
state: New York
city: Durham
country: United States
facility: Duke University Medical Center/Duke Cancer Center
state: North Carolina
city: Durham
country: United States
facility: Investigational Chemotherapy Service
state: North Carolina
city: Camperdown
country: Australia
facility: Chris O'Brien Lifehouse
state: New South Wales
city: Darlinghurst
country: Australia
facility: St Vincent's Hospital Sydney
state: New South Wales
city: Darlinghurst
country: Australia
facility: St Vincent's Public Hospital Sydney
state: New South Wales
city: St Albans
country: Australia
facility: Western Health, Sunshine Hospital
state: Victoria
city: Kingston
country: Canada
facility: Kingston Health Sciences Centre -
state: Ontario
city: Olomouc
country: Czechia
facility: Fakultni nemocnice Olomouc, Klinika nuklearni mediciny
city: Olomouc
country: Czechia
facility: Fakultni nemocnice Olomouc, Ustav klinicke a molekularni patologie
city: Olomouc
country: Czechia
facility: Fakultni nemocnice Olomouc
city: Prague
country: Czechia
facility: Thomayerova nemocnice
city: Prague
country: Czechia
facility: Thomayerova nemocnice
city: Prague
country: Czechia
facility: Centrum nuklearni mediciny s.r.o.
city: Prague
country: Czechia
facility: Centrum nuklearni mediciny s.r.o.
city: Praha 2
country: Czechia
facility: Vseobecna fakultni nemocnice v Praze
city: Praha 2
country: Czechia
facility: Vseobecna fakultni nemocnice v Praze
city: Praha 2
country: Czechia
facility: Vseobecna fakultni nemocnice v Praze
city: Praha 2
country: Czechia
facility: Vseobecna fakultni nemocnice v Praze
city: Budapest
country: Hungary
facility: Orszagos Onkologiai Intezet "C" Belgyogyaszati - Onkologiai es Klinikai Farmakologiai Osztaly
city: Torrette Di Ancona
country: Italy
facility: AOU Ospedali Riuniti di Ancona Umberto I - GM Lancisi - G Salesi
state: AN
city: Meldola
country: Italy
facility: IRCCS Istit.Scient.Romagnolo per lo Studio e la Cura dei Tumori
state: FC
city: Monza
country: Italy
facility: Centro di Ricerca di Fase 1, ASST Monza-Ospedale San Gerardo
state: MB
city: Monza
country: Italy
facility: Oncologia, ASST Monza-Ospedale San Gerardo
state: MB
city: Milano
country: Italy
facility: Istituto Europeo di Oncologia (IEO)
state: MI
city: Napoli
country: Italy
facility: Istituto Nazionale Tumori di Napoli IRCCS Fondazione Pascale
city: Barcelona
country: Spain
facility: Hospital Universitario Vall d'Hebron
city: Barcelona
country: Spain
facility: Hospital Clinic I Provincial
city: Madrid
country: Spain
facility: Hospital Universitario Fundacion Jimenez Diaz
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Valencia
country: Spain
facility: Fundacion Instituto Valenciano de Oncologia
city: Truro
country: United Kingdom
facility: Royal Cornwall Hospital
state: Cornwall
city: London
country: United Kingdom
facility: The Platinum Medical Centre
state: England
city: London
country: United Kingdom
facility: The Wellington Hospital - South
state: England
city: London
country: United Kingdom
facility: Sarah Cannon Research Institute UK
state: England
city: London
country: United Kingdom
facility: The Harley Street Clinic
state: England
city: London
country: United Kingdom
facility: HCA Pharmacy Department
state: England
city: London
country: United Kingdom
facility: The Harley Street Clinic
state: England
city: London
country: United Kingdom
facility: The Princess Grace Hospital
state: England
city: Sheffield
country: United Kingdom
facility: Weston Park Hospital
state: South Yorkshire
city: Newcastle upon Tyne
country: United Kingdom
facility: Sir Bobby Robson Cancer Trials Research Centre
Study officials:
affiliation: Pfizer
name: Pfizer CT.gov Call Center
role: STUDY_DIRECTOR
References: