Non-small Cell Lung Cancer Metastatic, Non-small Cell Lung Cancer Stage IIIB
Conditions
Keywords
NSCLC, tri-therapy, avelumab, axitinib, palbociclib, dual matched normal and tumor biopsies, SIMS algorithm, Sequencing, Gene expression
Brief summary
Patients with advanced/metastatic non-small cell lung cancer (NSCLC) with no documented targetable alterations (Epidermal Growth Factor Receptor (EGFR) mutation, Anaplastic Lymphoma Kinase (ALK) translocation, ROS1 mutation if available or MET exon 14 skipping mutation if available) will receive a tri-therapy associating avelumab, axitinib and palbociclib.
Detailed description
During the Phase 1 (approximately 30 patients), the tri-therapy will be tested at different doses following a specific dose-escalation scheme (3 + 3 model) in order to establish the safety and identify the Maximum Tolerated Dose (MTD) and recommended dose for the Phase 2 (RP2D). The phase 2 will confirm the safety and will assess the clinical utility of the tri-therapy approach in the treatment of advanced/metastatic NSCLC (100 patients). The study will also explore the clinical utility of the Simplified Interventional Mapping System (SIMS), a new tool/algorithm enabling matching of NSCLC patients with combination therapy. For this purpose tumor/metastasis and matched normal tissue biopsies will be requested in order to obtain sequencing and expression profiles.
Interventions
DRUGAvelumab
A human antibody of the immunoglobulin gamma-1 isotype that specifically targets and blocks the Programmed Death ligand (PD-L1) for PD-1.
DRUGAxitinib
A selective oral (tablet) inhibitor of tyrosine kinases Vascular Endothelial Growth Factor (VEGF) receptors 1, 2, and 3. These receptors are implicated in pathologic angiogenesis, tumor growth and cancer progression.
DRUGPalbociclib
A selective, reversible oral (capsule) inhibitor of cyclin-dependent kinases (CDK) 4 and 6. The inhibition of CDK 4/6 blocks DNA synthesis by prohibiting progression of the cell cycle from G1 to S phase.
Sponsors
ARC Foundation for Cancer Research
Pfizer
Worldwide Innovative Network Association
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
ELIGIBILITY CRITERIA * Age: Men and women aged \>18 years, * Signed written informed consent, * Any histologic type of locally advanced or metastatic NSCLC, * Life expectancy of ≥ 12 weeks, * Measurable or evaluable (cytologically or radiologically detectable disease such as ascites, peritoneal deposits, or lesions which do not fulfill RECIST 1.1 criteria for measurable disease) lesions according to RECIST 1.1 criteria for phase 1 portion. For phase 2, all patients must have RECIST 1.1 measurable disease, * Physiologic function: * Hematologic: Absolute neutrophil count (ANC) ≥ 1.5 × 109/L, platelet count ≥ 100 × 109/L, and hemoglobin ≥ 9 g/dL (may have been transfused), * Hepatic: Total bilirubin level ≤ 1.5 × the upper limit of normal (ULN) range and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels ≤ 2.5 × ULN, * Renal: Estimated creatinine clearance ≥ 30 mL/min according to the Cockcroft-Gault formula (or local institutional standard method). * Pregnancy and contraception: * Pregnancy test: Negative serum or urine pregnancy test at screening for women of childbearing potential. * Contraception: Highly effective contraception for both male and female subjects throughout the study and for at least 90 days after last treatment administration if the risk of conception exists. * Ability to comply with protocol requirements, * Willingness to consent and ability to undergo a trucut biopsy to obtain a fresh metastasis or primary tumor biopsy, and to undergo bronchoscopy to obtain a biopsy from normal bronchial mucosa, * No serious or medically uncontrolled concomitant conditions that are likely to make the patient unfit for SPRING combination therapy, as per investigator assessment, * ECOG performance status of 0 to 1.
Exclusion criteria
* Patients with documented oncogenic aberrations at enrollment: EGFR, ALK, ROS1 when available, MET exon 14 skipping when available. For squamous undifferentiated cell carcinoma, documentation of these aberrations is not mandatory. Note: For Phase 1 portion, all patients with adenocarcinoma histology must have documentation of results for druggable oncogenic aberrations (EGFR mutations, ALK rearrangements, and ROS1 when available) prior to enrollment on the study. * For Phase 1 portion, \>2 lines of prior therapy in the metastatic setting. * For the dose escalation phase of the study or until the MTD for the combination regimen has been determined, patients with moderate hepatic impairment defined as AST, ALT, alkaline phosphatase (ALP) \>5 times ULN, which would be grade 3 or higher. However, patients with liver metastases with AST/ALT ≤ 5 x ULN can be included in the study. * For Phase 2 portion, any prior therapy in the metastatic setting. Clinical criteria for phase 1 and phase 2 studies: * Patients with treated brain metastases are eligible as are patients with new, active untreated brain metastasis. * Participants with a history of myocardial infarction within the last 2 years or with significant cardiac arrhythmias uncontrolled by medication or pacemaker, * Participants with any history of interstitial lung disease, * Prior clinically significant toxicities from anticancer agents or radiotherapy which have not regressed to Grade ≤ 1 severity (NCI-CTCAE version 4.03) apart from peripheral neuropathy and alopecia, * History of any second malignancy in the last two years; patients with prior history of in-situ cancer or basal or squamous cell skin cancer are eligible. Patients with a history of other malignancies are eligible if they have been continuously disease-free for at least two years, * Autoimmune condition requiring medical intervention, * Uncontrolled concomitant illness, active infection requiring i.v. antibiotics, * Patients who have had a thromboembolic event within six months are excluded, as are patients on anticoagulants, except for low dose aspirin (\<100 mg/day) and low doses of anticoagulants meant to keep line access open; * Patients with Grade 3 or 4 (serious) gastrointestinal bleeding within the last six months are excluded. * Prior \> G3 hemoptysis, major blood vessel involvement (specifically including aorta, superior and inferior vena cave, main pulmonary arteries and veins, subclavian arteries and veins and other large blood vessels that in the investigator's opinion places the patients at high risk for major bleeding), and/or central cavitations, * Known or suspected drug hypersensitivity to any drug used in the combination, * Difficulty swallowing, malabsorption or other chronic gastrointestinal disease, or conditions that may hamper compliance and/or absorption of the oral drugs, * Any condition (e.g., known or suspected poor compliance, psychological instability, geographical location, etc.) that, in the judgment of the investigator may affect the patient's ability to sign the informed consent and undergo study procedures, * Taking another experimental drug within 28 days prior to day 1 of the protocol medications in this study, * Pregnant or breast-feeding women, * Both male and female patients of reproductive potential must agree to use highly effective contraception, during the study and for 3 months following the last dose of study drug, * Patients currently taking strong CYP3A4 inducers and inhibitors, * Patients currently taking proton pump inhibitors due to their impact on the disposition of palbociclib during the phase 1. * Patients taking other anticancer agents with the exception of denosumab or equivalent medication for bone metastases. * A time period of at least three weeks (including radiotherapy) or five drug half-lives, whichever is shorter must have elapsed from last non-investigational therapy before first day of treatment on this study, * A time period of at least 10 days must have elapsed from last palliative radiotherapy before the first day of treatment on this study, * Specific
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| SIMS Algorithm to Predict Clinical Outcome | 4 years | The proportion of participants whose SIMS analysis matches the treatment combination, will be correlated retrospectively to clinical outcome. |
| Progression-Free Survival (PFS) | 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 1.1 or death due to any cause, whichever occurs first. |
| Overall Survival (OS) | Baseline up to approximately 24 months | OS is defined as the time from the first dose of study treatment to the date of death due to any cause. |
| Incidence of the Tested 3-Drug Combination Therapy-Emergent Adverse Events and Serious Adverse Events | From informed consent signature through 90 days after administration of the treatment (last dose) | The occurrence of adverse events and serious adverse events reported from the signing of an informed consent through 90 days after the last administration of the treatment will be summarized for all subjects who received at least one dose of the study treatment (safety population) and will be evaluated based on NCI CTCAE v4.03: June 14, 2010. |
| Response Rate (RR) | Baseline up to approximately 24 months | Response rate is defined as the proportion of participants with reduction in tumor burden of a predefined amount based on RECIST 1.1 evaluation |
| Duration of the Response | Baseline up to approximately 24 months | Duration of Response (DR) is defined for patients with confirmed objective response (Complete Response \[CR\] or Partial Response \[PR\]) 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Genomic and Transcriptomic Profile | 4 years | Genomic (DNA) and transcriptomic (RNA) aberrations (mutations, translocations, rearrangements and changes in expression level) identified in the study population (Non-Small Cell Lung) will be described. |
| Incidence of Treatment-related and or Biopsy-related Serious Adverse Events | 4 years | The occurrence of treatment-related and or biopsy-related serious adverse events as assessed by NCI CTCAE v4.03 will be summarized for all study subjects. |
Countries
Israel, Luxembourg, Spain, United States
Participant flow
Recruitment details
A total of 15 patients were recruited in the Phase 1 part of the study in 5 centers across 4 countries (Luxembourg, Israel, Spain and USA). The study was early terminated prior starting the Phase 2 due to lack of fundings. The following number of treated patients were initially planned to be recruited: up to 30 in the Phase 1 and 100 in the Phase 2.
Pre-assignment details
Patients with advanced/metastatic advanced/metastatic non-small cell lung cancer (NSCLC) with no documented targetable alterations (EGFR mutation, ALK translocation, ROS1 mutation if available or MET exon 14 skipping mutation if available) were recruited in the study.
Participants by arm
| Arm | Count |
|---|---|
| Dose Level 1 Non-small cell lung cancer (NSCLC) patients treated with avelumab (10 mg/kg IV every two weeks -1/+3 days, on day 1 and day 15 of a 28 day cycle), axitinib (3 mg taken orally twice a day, every day of a 28 day cycle) and palbociclib (75 mg taken orally, daily on days 8-28 of a 28 day cycle). | 6 |
| Dose Level 2 Non-small cell lung cancer (NSCLC) patients treated with avelumab (10 mg/kg IV every two weeks -1/+3 days, on day 1 and day 15 of a 28 day cycle), axitinib (5 mg taken orally twice a day, every day of a 28 day cycle) and palbociclib (75 mg taken orally, daily on days 8-28 of a 28 day cycle). | 6 |
| Dose Level 3 Non-small cell lung cancer (NSCLC) patients treated with avelumab (10 mg/kg IV every two weeks -1/+3 days, on day 1 and day 15 of a 28 day cycle), axitinib (5 mg taken orally twice a day, every day of a 28 day cycle) and palbociclib (100 mg taken orally, daily on days 8-28 of a 28 day cycle). | 3 |
| Total | 15 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Clinical Monitoring Committee and physician choice | 1 | 1 | 1 |
| Overall Study | Death | 0 | 0 | 1 |
| Overall Study | Physician Decision | 0 | 0 | 1 |
| Overall Study | Progression | 4 | 4 | 0 |
| Overall Study | Transfer to SPRING Rollover protocol (EU CT # 2022-500041-24-00) after closing SPRING | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Total | Dose Level 1 | Dose Level 2 | Dose Level 3 |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 8 Participants | 3 Participants | 4 Participants | 1 Participants |
| Age, Categorical Between 18 and 65 years | 7 Participants | 3 Participants | 2 Participants | 2 Participants |
| Age, Continuous | 67 years | 68 years | 67 years | 54 years |
| Race/Ethnicity, Customized Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Black | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Caucasian | 14 Participants | 6 Participants | 6 Participants | 2 Participants |
| Race/Ethnicity, Customized Mexican | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Region of Enrollment Israel | 3 participants | 0 participants | 2 participants | 1 participants |
| Region of Enrollment Luxembourg | 2 participants | 0 participants | 2 participants | 0 participants |
| Region of Enrollment Spain | 3 participants | 1 participants | 2 participants | 0 participants |
| Region of Enrollment United States | 7 participants | 5 participants | 0 participants | 2 participants |
| Sex: Female, Male Female | 5 Participants | 3 Participants | 1 Participants | 1 Participants |
| Sex: Female, Male Male | 10 Participants | 3 Participants | 5 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 6 | 1 / 6 | 1 / 3 |
| other Total, other adverse events | 6 / 6 | 6 / 6 | 3 / 3 |
| serious Total, serious adverse events | 3 / 6 | 4 / 6 | 2 / 3 |
Outcome results
Primary
Duration of the Response
Duration of Response (DR) is defined for patients with confirmed objective response (Complete Response \[CR\] or Partial Response \[PR\]) 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.
Time frame: Baseline up to approximately 24 months
Population: This outcome could not be measured because the data were not collected. Indeed, the trial was early terminated after the end of the phase 1. The phase 2 was not started, no data can be reported.
Primary
Incidence of the Tested 3-Drug Combination Therapy-Emergent Adverse Events and Serious Adverse Events
The occurrence of adverse events and serious adverse events reported from the signing of an informed consent through 90 days after the last administration of the treatment will be summarized for all subjects who received at least one dose of the study treatment (safety population) and will be evaluated based on NCI CTCAE v4.03: June 14, 2010.
Time frame: From informed consent signature through 90 days after administration of the treatment (last dose)
Population: This outcome could not be measured because the data were not collected. Indeed, the trial was early terminated after the end of the phase 1. The phase 2 was not started, no data can be reported.
Primary
Overall Survival (OS)
OS is defined as the time from the first dose of study treatment to the date of death due to any cause.
Time frame: Baseline up to approximately 24 months
Population: This outcome could not be measured because the data were not collected. Indeed, the trial was early terminated after the end of the phase 1. The phase 2 was not started, no data can be reported.
Primary
Progression-Free Survival (PFS)
Progression Free Survival (PFS) is defined as the time from the first dose of study treatment to the date of disease progression by RECIST 1.1 or death due to any cause, whichever occurs first.
Time frame: Baseline up to approximately 24 months
Population: This outcome could not be measured because the data were not collected. Indeed, the trial was early terminated after the end of the phase 1. The phase 2 was not started, no data can be reported.
Primary
Response Rate (RR)
Response rate is defined as the proportion of participants with reduction in tumor burden of a predefined amount based on RECIST 1.1 evaluation
Time frame: Baseline up to approximately 24 months
Population: This outcome could not be measured because the data were not collected. Indeed, the trial was early terminated after the end of the phase 1. The phase 2 was not started, no data can be reported.
Primary
SIMS Algorithm to Predict Clinical Outcome
The proportion of participants whose SIMS analysis matches the treatment combination, will be correlated retrospectively to clinical outcome.
Time frame: 4 years
Population: This outcome could not be measured because the data were not collected. Indeed, the trial was early terminated after the end of the phase 1. The phase 2 was not started, no data can be reported.
Secondary
Genomic and Transcriptomic Profile
Genomic (DNA) and transcriptomic (RNA) aberrations (mutations, translocations, rearrangements and changes in expression level) identified in the study population (Non-Small Cell Lung) will be described.
Time frame: 4 years
Population: This outcome could not be measured because the data were not collected. Indeed, the trial was early terminated after the end of the phase 1. The phase 2 was not started, no data can be reported.
Secondary
Incidence of Treatment-related and or Biopsy-related Serious Adverse Events
The occurrence of treatment-related and or biopsy-related serious adverse events as assessed by NCI CTCAE v4.03 will be summarized for all study subjects.
Time frame: 4 years
Population: This outcome could not be measured because the data were not collected. Indeed, the trial was early terminated after the end of the phase 1. The phase 2 was not started, no data can be reported.