A Study of Avelumab in Combination With Axitinib In Non-Small Cell Lung Cancer (NSCLC) or Urothelial Cancer (Javelin Medley VEGF)

Phase 2TerminatedNCT03472560

Pfizer61 enrolled

Overview

This is a Phase 2 study to evaluate the safety and efficacy of avelumab in combination with axitinib in patients with advanced or metastatic non-small cell lung cancer (NSCLC) who have received at least one prior platinum containing therapy, and in treatment naïve patients with advanced or metastatic urothelial cancer, who are ineligible for cisplatin containing chemotherapy for their advanced disease.

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Non-Small Cell Lung Cancer Urothelial Cancer

Interventions

Avelumab (MSB0010718C)DRUG

IV treatment: Avelumab administered at 800 mg IV every two weeks

Axitinib (AG-013736)DRUG

Oral treatment: Axitinib given 5 mg PO BID

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Non-small cell lung cancer (NSCLC) Cohort: Histologically or cytologically confirmed diagnosis of NSCLC that is locally advanced or metastatic; No activating EGFR mutations, ALK or ROS1 translocations/rearrangements where testing is standard of care; received at least 1 prior platinum-based chemotherapy regimen for locally advanced or metastatic NSCLC; No more than 2 prior lines of systemic therapy for locally advanced or metastatic disease (If disease progression occurred during or within 6 months after neoadjuvant/adjuvant chemotherapy or radiotherapy-chemotherapy, the regimen is counted as 1 prior treatment regimen towards the allowed limit of prior treatment regimens); Checkpoint inhibitor naïve. * Urothelial Cancer (UC) Cohort: Histologically or cytologically confirmed diagnosis of transitional cell carcinoma (TCC) of the urothelium (if mixed, more than 50% TCC component) including bladder, urethra, ureters, or renal pelvis that is locally advanced or metastatic; No prior systemic treatment for locally advanced or metastatic disease; Prior neoadjuvant or adjuvant therapy is permitted if disease progression occurred \>12 months after the completion of therapy; Checkpoint inhibitor naïve; Ineligible for receiving cisplatin-containing front-line chemotherapy based at least one of the following criteria: ECOG performance status (PS) 2; Renal dysfunction (defined as creatinine-clearance \<60 ml/min); Grade 2 peripheral neuropathy; Grade 2 hearing loss (hearing loss measured by audiometry of 25 decibels at two contiguous frequencies). * At least 1 measurable lesion by RECIST v1.1 not previously irradiated. * Availability of an archival FFPE tumor tissue block from primary diagnosis specimen or metastatic specimen or 15 unstained slides (10 minimum). If an archived sample is not available, a fresh tumor biopsy must be performed. * Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. For UC patients, ECOG performance 2 is permitted (cisplatin ineligibility criterion) Exclusion Criteria: * Prior immunotherapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, anti-OX-40, anti-GITR, anti-LAG-3, anti-TIM-3 or anti-CTLA-4 antibody (including ipilimumab). * Newly diagnosed brain metastases or known symptomatic brain metastases requiring steroids. * Radiologically documented evidence of major blood vessel invasion or encasement by cancer or intratumor cavitation, regardless of tumor histology. * Active autoimmune disease (that might deteriorate when receiving an immunostimulatory agent). * Current use of immunosuppressive medication (except for those listed in protocol). * Known prior severe hypersensitivity to the investigational products /monoclonal antibodies. * Known history of immune-mediated colitis, inflammatory bowel disease, immune-mediated pneumonitis, pulmonary fibrosis. * NCI CTCAE Grade 3 hemorrhage within 28 days prior to study enrollment.

Locations (39)

Outcomes

Primary Outcomes

Percentage of Participants With Confirmed Objective Response- Objective Response Rate (ORR)

ORR: percentage of participants with a confirmed Complete Response (CR) or Partial Response (PR) based on investigator's assessment as per Response Evaluation Criteria in Solid Tumours (RECIST version \[v\] 1.1). Both CR and PR were confirmed by repeat assessments performed no less than 4 weeks after criteria for response was first met. Per RECIST v1.1: CR was defined as complete disappearance of all target lesions and non-target disease, with exception of nodal disease. All nodes, both target and non-target, must decrease to normal (short axis less than \[\<\]10 millimeter \[mm\]). No new lesions. PR was defined as greater than or equal to (\>=) 30 percent (%) decrease under baseline of sum of diameters of all target lesions. Short axis was used in sum for target nodes, while longest diameter was used in sum for all other target lesions. No unequivocal progression of non-target disease. No new lesions. Stable disease was defined as not qualifying for CR, PR, Progressive Disease.

Time frame: Baseline up to 56 months

Secondary Outcomes

Percentage of Participants With Treatment Emergent Adverse Events (TEAEs) During the On-Treatment Period

An Adverse Event (AE) was any untoward medical occurrence attributed to study drug in a participant who received avelumab or axitinib. Treatment-emergent adverse events (TEAEs) were those events with onset dates occurring during the on-treatment period (the time from the first dose of study treatment through minimum 30 days post last dose of study treatment or start day of new anti-cancer treatment -1 day).

Time frame: From first dose of study treatment (Day 1) up to 30 days post last dose of study treatment or start of new anti-cancer treatment -1 day (maximum up to 56 months)

Percentage of Participants With Hematology Test Results of Maximum National Cancer Institute; Common Terminology Criteria for Adverse Events (NCI CTCAE) Grade During the On-Treatment Period

The following hematology parameters were assessed: anemia, hemoglobin increased, international normalized ratio (INR) increased, lymphocyte count decreased, lymphocyte count increased, neutrophil count decreased, platelet count decreased and white blood cell decreased. Laboratory abnormality events were graded according to NCI CTCAE v 4.03 (grade 3= severe and grade 4= life-threatening). Categories with non-zero values are presented.

Data from ClinicalTrials.gov

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Arizona Oncology Associates- Saguaro Cancer Center

Glendale, Arizona, United States

Arizona Oncology Associates

Goodyear, Arizona, United States

Arizona Oncology Associates- Biltmore Cancer Center

Phoenix, Arizona, United States

Arizona Oncology Associates- Deer Valley Cancer Center

Phoenix, Arizona, United States

Arizona Oncology Associates- East Valley Cancer Center

Tempe, Arizona, United States

The Oncology Institute of Hope and Innovation

Glendale, California, United States

The Oncology Institute of Hope and Innovation

Long Beach, California, United States

The Oncology Institute of Hope and Innovation

Santa Ana, California, United States

The Oncology Institute of Hope and Innovation

Whittier, California, United States

Oncology Hematology Associates

Springfield, Missouri, United States

...and 29 more locations

Time frame: From first dose of study treatment (Day 1) up to 30 days post last dose of study treatment or start of new anti-cancer treatment -1 day (maximum up to 56 months)

Percentage of Participants With Chemistry Test Results of Maximum CTCAE Grade During the On-Treatment Period

The following chemistry parameters were assessed: alanine aminotransferase increased, alkaline phosphatase increased, aspartate aminotransferase increased, blood bilirubin increased, cholesterol high, creatine phosphokinase (CPK) increased, creatinine increased, gamma-glutamyl transferase (GGT) increased, hypercalcemia, hyperglycemia, hyperkalemia, hypermagnesemia, hypernatremia, hypertriglyceridemia, hypoalbuminemia, hypocalcemia, hypoglycemia, hypokalemia, hypomagnesemia, hyponatremia, hypophosphatemia, lipase increased and serum amylase increased. Laboratory abnormalities were graded according CTCAE version 4.03 (grade 3= severe, grade 4= life-threatening and grade 5= death related). Categories with non-zero values are presented.

Time frame: From first dose of study treatment (Day 1) up to 30 days post last dose of study treatment or start of new anti-cancer treatment -1 day (maximum up to 56 months)

Time to Tumor Response (TTR) in Participants With Confirmed CR or PR

TTR was defined as the time from the first dose of study treatment to the first documentation of objective tumor response documented in participants with confirmed objective response (CR or PR). CR was defined as complete disappearance of all target lesions and non-target disease, with the exception of nodal disease. All nodes, both target and non-target, must decrease to normal (short axis \<10 mm). No new lesions. PR was defined as \>=30% decrease under baseline of the sum of diameters of all target lesions. The short axis was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. No unequivocal progression of non-target disease. No new lesions. Analysis was performed using Kaplan-Meier method.

Time frame: From date of start of treatment until date of first documentation of objective tumor response (maximum up to 56 months)

Duration of Response in Participants With Confirmed CR or PR

Duration of response was defined 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 occurred first in participants with confirmed objective response (CR or PR). CR was defined as complete disappearance of all target lesions and non-target disease, with the exception of nodal disease. All nodes, both target and non-target, must decrease to normal (short axis \<10 mm). No new lesions. PR was defined as \>=30% decrease under baseline of the sum of diameters of all target lesions. The short axis was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. No unequivocal progression of non-target disease. No new lesions. Analysis was performed using Kaplan-Meier method.

Time frame: From date of first documentation of objective tumor response to the first documentation of objective tumor progression or to death due to any cause, whichever occurred first (maximum up to 56 months)

Progression Free Survival (PFS)

PFS was defined as the time from first dose of study treatment (ie, start date) to the date of progression of disease (PD) by RECIST v 1.1 or death due to any cause, whichever occurred first. PFS data was censored on the date of the last adequate tumor assessment for participants without an event (PD or death), for participants who started new anti-cancer treatment prior to an event, or for participants with an event after two or more missing tumor assessments. PD as per RECIST v1.1 for target lesions was defined as 20% increase in the sum of diameters of target measurable lesions above the smallest sum observed (over baseline if no decrease in the sum is observed during therapy), with a minimum absolute increase of 5 mm. For non-target lesions PD was defined as unequivocal progression of pre-existing lesions. Analysis was performed using Kaplan-Meier method.

Time frame: From start of study treatment until first documentation of PD or death due to any cause or censoring date (maximum of 24 months)

Overall Survival

Overall survival was defined as the time from the date of first study treatment to the date of death due to any cause. Participants last known to be alive were censored at date of last contact. Analysis was performed using Kaplan-Meier method.

Time frame: From date of start of study treatment until date of death or censoring date (maximum up to 56 months)

Maximum Observed Serum Concentration (Cmax) of Avelumab

Time frame: Pre-dose, 1 hour post-dose on Cycle 1 Day 1, Day 15 and Cycle 2 Day 1

Cmax of Axitinib

Time frame: Pre-dose, 2 hour post-dose on Cycle 1 Day 15, Cycle 2 Day 1 and 15

Pre-dose Observed Serum Concentration (Ctrough) of Avelumab

Time frame: Pre-dose on Cycle 1 Day 1, 15, Cycle 2 Day 1, Cycle 3 Day 15, Cycle 6 Day 15, Cycle 9 Day 15, and Cycle 12 Day 15

Ctrough of Axitinib

Time frame: Pre-dose on Cycle 1 Day 15, Cycle 2 Day 1 and 15

Number of Participants With Programmed Death-Ligand 1 (PD-L1) Status

PD-L1 status was defined as positive when PD-L1 staining of any intensity was observed in \>= 1% of the tumor cells. PD-L1 status was defined as negative when PD-L1 staining of any intensity was observed in \< 1% of the tumor cells.

Time frame: Screening, up to 28 days prior to Day 1

Tumour Mutational Burden (TMB) in Tumor Tissue

Mutational load within tumor tissue was defined as number per megabase of the genome, coding, base substitution, and indel mutations present in the sample. Mutational load was determined in whole blood samples using next generation deoxyribonucleic acid (DNA) sequencing followed by computational analysis.

Time frame: Screening, up to 28 days prior to Day 1

T-cell Receptor (TCR) Sequencing to Identify Fraction Productive of Cells

The immune response was measured by total T cell receptor (TCR) sequencing in peripheral blood and determined the characterization of immune repertoires. Fraction productive of cells is defined as the number of T cells within the total nucleated cell count (T cells and non-T cells).

Time frame: Screening, up to 28 days prior to Day 1

T-cell Receptor (TCR) Sequencing to Identify Simpson Clonality

The immune response was measured by TCR sequencing in peripheral blood and determined the characterization of immune repertoires. Simpson clonality is calculated for a sample as the square root of Simpson's diversity index for all productive rearrangements. Values for clonality ranged from 0 to 1. Values near 1 represented samples with one or a few predominant rearrangements (monoclonal or oligoclonal samples) dominating the observed repertoire. Clonality values near 0 represented more polyclonal samples.

Time frame: Pre-dose on Day 1 of Cycle 1

T-cell Receptor (TCR) Sequencing to Identify Total T Cells

The immune response was measured by total TCR sequencing in peripheral blood and determined the characterization of immune repertoires.

Time frame: Pre-dose on Day 1 of Cycle 1

Number of Participants With Positive Anti-drug Antibody (ADA) and Neutralizing Antibodies (nAb) Against Avelumab

ADA and nAb positive was defined as presence of at least one positive ADA and nAb sample, respectively. NAb analysis was planned to be conducted for ADA positive samples.

Time frame: Within 2 hours pre-dose on Cycle 1 Day 1,15, Cycle 2 Day 1; Day 15 of Cycle 3, 6, 9, 12, end of treatment and 30 days after last dose of study treatment (maximum up to 56 months)