Clinical Trials /

Survival Prolongation by Rationale Innovative Genomics

NCT03386929

Description:

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.

Related Conditions:
  • Lung Adenocarcinoma
  • Non-Small Cell Lung Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Survival Prolongation by Rationale Innovative Genomics
  • Official Title: A Proof of Concept Study to Explore Safety and Efficacy of Tri-therapy Approach in Advanced/Metastatic NSCLC and Retrospectively Assess the Ability of Integrated Genomics and Transcriptomics to Match Patients to the Combination

Clinical Trial IDs

  • ORG STUDY ID: WIN001
  • SECONDARY ID: 2017-001455-32
  • NCT ID: NCT03386929

Conditions

  • Non-small Cell Lung Cancer Metastatic
  • Non-Small Cell Lung Cancer Stage IIIB

Interventions

DrugSynonymsArms
AvelumabBavencioAvelumab, Axitinib, Palbociclib
AxitinibInlytaAvelumab, Axitinib, Palbociclib
PalbociclibIbranceAvelumab, Axitinib, Palbociclib

Purpose

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 (RP2D) for the
      Phase 2. 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.
    

Trial Arms

NameTypeDescriptionInterventions
Avelumab, Axitinib, PalbociclibExperimentalFor the Phase 1: Avelumab is administered intravenously (IV) on Day 1 and Day 15 of each Cycle (one cycle = 28 days) in combination with axitinib po bid and palbociclib po (7 days off; 21 days on). For the Phase 2: Avelumab, axitinib and palbociclib are administered at the recommended dose (RP2D) as determined during the phase 1 part of the study.
  • Avelumab
  • Axitinib
  • Palbociclib

Eligibility Criteria

        INCLUSION CRITERIA:

          1. Age: Men and women aged ≥ 18 years,

          2. Signed written informed consent,

          3. Any histologic type of locally advanced or metastatic NSCLC,

          4. Life expectancy of ≥ 12 weeks,

          5. 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 v1.1 criteria for phase 1 portion. For
             phase 2, all patients must have RECIST 1.1 measurable disease,

          6. Physiologic function:

               -  Hematologic function: Absolute neutrophil count (ANC) ≥ 1.5 × 109/L, platelet
                  count ≥ 100 × 109/L, and hemoglobin ≥ 9 g/dL (may have been transfused),

               -  Hepatic function: 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 function: Estimated creatinine clearance ≥ 30 mL/min according to the
                  Cockcroft-Gault formula (or local institutional standard method).

          7. 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 90 days after last avelumab treatment administration
                  if the risk of conception exists.

          8. Ability to comply with protocol requirements,

          9. Willingness to consent and ability to undergo a trucut biopsy to obtain a fresh
             metastasis or primary tumor biopsy in case no adequate tumoral tissue is available,
             and to undergo fibroscopy to obtain a biopsy from normal bronchial mucosa,

         10. No serious or medically uncontrolled concomitant conditions that are likely to make
             the patient unfit for SPRING combination therapy, as per investigator assessment,

         11. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.

        EXCLUSION CRITERIA:

          1. Patients with documented oncogenic aberrations at enrollment: EGFR, ALK, ROS1 when
             available, MET exon 14 skipping when available.

             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.

          2. For Phase 1 portion, >2 lines of prior therapy in the metastatic setting.

          3. 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.

          4. For Phase 2 portion, any prior therapy in the metastatic setting.

        Clinical exclusion criteria for Phase 1 and Phase 2 studies:

          1. Documented untreated central nervous system metastases (indicated by clinical
             symptoms, cerebral edema, steroid requirement, or progressive disease in the prior
             four weeks),

          2. Participants with a history of myocardial infarction within the last 2 years or with
             significant cardiac arrhythmias uncontrolled by medication or pacemaker,

          3. Participants with any history of interstitial lung disease,

          4. 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,

          5. 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,

          6. Autoimmune condition requiring medical intervention,

          7. Uncontrolled concomitant illness, active infection requiring i.v. antibiotics,

          8. Participants who are at risk for, or who have a history of arterial thromboembolic
             events within the past 12 months and/or venous thromboembolic events within the past 6
             months, or have had any recent active gastrointestinal bleeding,

          9. Prior > G3 hemoptysis, major blood vessel involvement, and/or central cavitations,

         10. Known or suspected drug hypersensitivity to any drug used in the combination,

         11. Difficulty swallowing, malabsorption or other chronic gastrointestinal disease, or
             conditions that may hamper compliance and/or absorption of the oral drugs,

         12. 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,

         13. Taking another experimental drugs within 28 days prior to day 1 of the protocol
             medications in this study,

         14. Pregnant or breast-feeding women,

         15. Both male and female patients of reproductive potential must agree to use a reliable
             method of birth control, during the study and for 3 months following the last dose of
             study drug,

         16. Patients currently taking strong CYP3A4 inducers and inhibitors.

         17. Patients currently taking proton pump inhibitors due to their impact on the
             disposition of palbociclib during the dose escalation phase,

         18. Other anticancer agents and anticoagulants are excluded (except for low doses of
             anticoagulants used for access lines)

         19. A time period of at least three weeks or five drug half-lives, whichever is shorter
             must have elapsed from last non-investigational therapy before day 1 of treatment on
             this study,

         20. Specific exclusion criteria for administration of avelumab, in combination:

               -  IMMUNOSUPRESSANTS: Current use of immunosuppressive medication, EXCEPT for the
                  following: a. intranasal, inhaled, topical steroids, or local steroid injection
                  (e.g., intra-articular injection); b. Systemic corticosteroids at physiologic
                  doses ≤ 10 mg/day of prednisone or equivalent; c. Steroids as premedication for
                  hypersensitivity reactions (e.g., CT scan premedication).

               -  AUTOIMMUNE DISEASE: Active autoimmune disease that might deteriorate when
                  receiving an immuno-stimulatory agent. Patients with diabetes type I, vitiligo,
                  psoriasis, or hypo- or hyperthyroid diseases not requiring immunosuppressive
                  treatment are eligible.

               -  ORGAN TRANSPLANTATION: Prior organ transplantation including allogenic stem-cell
                  transplantation.

               -  INFECTIONS: Active infection requiring systemic therapy.

               -  HIV/AIDS: Known history of testing positive for HIV or known acquired
                  immunodeficiency syndrome.

               -  HEPATITIS: Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at
                  screening (positive HBV surface antigen or HCV RNA if anti-HCV antibody screening
                  test positive).

               -  VACCINATION: Vaccination within 4 weeks of the first dose of avelumab and while
                  on trials is prohibited except for administration of inactivated vaccines.

               -  HYPERSENSITIVITY TO STUDY DRUG: Known prior severe hypersensitivity to
                  investigational product or any component in its formulations, including known
                  severe hypersensitivity reactions to monoclonal antibodies (NCI CTCAE v4.03 Grade
                  ≥ 3).

               -  CARDIOVASCULAR DISEASE: Clinically significant (i.e., active) cardiovascular
                  disease: cerebral vascular accident/stroke (< 6 months prior to enrollment),
                  myocardial infarction (< 6 months prior to enrollment), unstable angina,
                  congestive heart failure (≥ New York Heart Association Classification Class II),
                  or serious cardiac arrhythmia requiring medication.

               -  OTHER PERSISTING TOXICITIES: Persisting toxicity related to prior therapy (NCI
                  CTCAE v. 4.03 Grade > 1); however, alopecia, sensory neuropathy Grade ≤ 2, or
                  other Grade ≤ 2 not constituting a safety risk based on investigator's judgment
                  are acceptable.

               -  Other severe acute or chronic medical conditions including colitis, inflammatory
                  bowel disease, pneumonitis, pulmonary fibrosis or psychiatric conditions
                  including recent (within the past year) or active suicidal ideation or behavior;
                  or laboratory abnormalities that may increase the risk associated with study
                  participation or study treatment administration or may interfere with the
                  interpretation of study results and, in the judgment of the investigator, would
                  make the patient inappropriate for entry into this study.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Dose Limiting Toxicity (DLT)
Time Frame:Cycle 1 Days 1-28 (28 days from date of first dose of study treatment)
Safety Issue:
Description:DLT is assessed by NCI CTCAE v4.03

Secondary Outcome Measures

Measure:Incidence of Treatment-related and or Biopsy-related Serious Adverse Events
Time Frame:4 years
Safety Issue:
Description: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.
Measure:Genomic and Transcriptomic Profile
Time Frame:4 years
Safety Issue:
Description: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.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Worldwide Innovative Networking Association

Trial Keywords

  • NSCLC
  • tri-therapy
  • avelumab
  • axitinib
  • palbociclib
  • dual matched normal and tumor biopsies
  • SIMS algorithm
  • Sequencing
  • Gene expression

Last Updated

January 3, 2018