Clinical Trials /

Testing the Addition of an Anti-cancer Drug, M6620, to the Usual Treatments (Carboplatin and Gemcitabine) and to Avelumab for Non-small Cell Lung Cancer

NCT04216316

Description:

This phase Ib/II trial studies the best dose of carboplatin when given together with M6620, gemcitabine and avelumab and to see how well it works in treating patients with stage IV squamous cell non-small cell lung cancer. M6620 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Chemotherapy drugs, such as carboplatin and gemcitabine, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Immunotherapy with monoclonal antibodies, such as avelumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving M6620 together with carboplatin, gemcitabine, and avelumab may work better in treating patients with squamous cell non-small cell lung cancer compared to carboplatin, gemcitabine, and avelumab alone.

Related Conditions:
  • Squamous Cell Lung Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Testing the Addition of an Anti-cancer Drug, M6620, to the Usual Treatments (Carboplatin and Gemcitabine) and to Avelumab for Non-small Cell Lung Cancer
  • Official Title: A Phase IB and Randomized Open-Label Phase II Study of M6620 in Combination With Carboplatin/Gemcitabine/Avelumab in Patients With Chemotherapy-Naive Advanced Non-Small Cell Lung Cancer of Squamous Cell Histology

Clinical Trial IDs

  • ORG STUDY ID: NCI-2019-08660
  • SECONDARY ID: NCI-2019-08660
  • SECONDARY ID: 10313
  • SECONDARY ID: 10313
  • SECONDARY ID: UM1CA186690
  • NCT ID: NCT04216316

Conditions

  • Lung Non-Small Cell Squamous Carcinoma
  • Stage IV Lung Cancer AJCC v8

Interventions

DrugSynonymsArms
AvelumabBavencio, MSB-0010718C, MSB0010718CArm A (avelumab, gemcitabine, carboplatin, M6620)
Berzosertib2-Pyrazinamine, 3-(3-(4-((Methylamino)methyl)phenyl)-5-isoxazolyl)-5-(4-((1-methylethyl)sulfonyl)phenyl)-, M 6620, M6620, VX 970, VX-970, VX970Arm A (avelumab, gemcitabine, carboplatin, M6620)
CarboplatinBlastocarb, Carboplat, Carboplatin Hexal, Carboplatino, Carboplatinum, Carbosin, Carbosol, Carbotec, CBDCA, Displata, Ercar, JM-8, Nealorin, Novoplatinum, Paraplatin, Paraplatin AQ, Paraplatine, Platinwas, RibocarboArm A (avelumab, gemcitabine, carboplatin, M6620)
Gemcitabine HydrochloridedFdCyd, Difluorodeoxycytidine Hydrochloride, FF 10832, FF-10832, FF10832, Gemcitabine HCI, Gemzar, LY-188011, LY188011Arm A (avelumab, gemcitabine, carboplatin, M6620)

Purpose

This phase Ib/II trial studies the best dose of carboplatin when given together with M6620, gemcitabine and avelumab and to see how well it works in treating patients with stage IV squamous cell non-small cell lung cancer. M6620 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Chemotherapy drugs, such as carboplatin and gemcitabine, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Immunotherapy with monoclonal antibodies, such as avelumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving M6620 together with carboplatin, gemcitabine, and avelumab may work better in treating patients with squamous cell non-small cell lung cancer compared to carboplatin, gemcitabine, and avelumab alone.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the recommended phase 2 dose (RP2D) of carboplatin in combination with
      berzosertib (M6620) and gemcitabine/avelumab, in patients with squamous cell non-small cell
      lung cancer (Sq-NSCLC). (Lead-in Phase 1B) II. To compare progression-free survival (PFS) of
      carboplatin/gemcitabine/avelumab with and without M6620 in patients with Sq-NSCLC, as
      measured by a hazard ratio in an intent-to-treat analysis. (Phase 2)

      SECONDARY OBJECTIVES:

      I. To compare progression-free survival (PFS) of carboplatin/gemcitabine/avelumab with and
      without M6620 in patients with Sq-NSCLC, as measured by a hazard ratio in an as-treated
      analysis.

      II. To compare PFS of carboplatin/gemcitabine/avelumab with and without M6620 in patients
      with ataxia telangiectasia mutated (ATM)-deficient Sq-NSCLC, as measured by a hazard ratio.

      III. To compare overall survival (OS) and overall response rate (ORR) of
      carboplatin/gemcitabine/avelumab with and without M6620, in patients with chemotherapy-naive
      Sq-NSCLC.

      IV. To determine the systemic drug exposure of M6620 and gemcitabine, as correlates of
      efficacy and toxicity.

      V. To determine the safety and tolerability of M6620 in combination with
      carboplatin/gemcitabine/avelumab.

      VI. To observe and record anti-tumor activity.

      EXPLORATORY OBJECTIVES:

      I. To identify molecular subpopulations of patients who have increased sensitivity to the
      M6620/carboplatin/gemcitabine/avelumab combination.

      II. To explore the prognostic and predictive qualities of the ATM immunohistochemistry (IHC)
      assay for clinical response and PFS.

      III. To explore inflammation-associated gene signatures and clinical response.

      OUTLINE: This is a phase Ib, dose de-escalation study of carboplatin followed by a phase II
      study. Patients are randomized to 1 of 2 arms.

      ARM A: Patients receive avelumab intravenously (IV) over 60 minutes and gemcitabine
      hydrochloride IV over 30 minutes on days 1 and 8. Patients also receive carboplatin IV over
      30 minutes on day 1 and berzosertib IV over 60 minutes on days 2 and 9. Treatment repeats
      every 21 days for up to 4 cycles in the absence of disease progression or unacceptable
      toxicity. Patients also receive avelumab IV over 60 minutes on days 1 and 8 and berzosertib
      IV over 60 minutes on days 2 and 9. Cycles repeat every 21 days for up to 9 months in the
      absence of disease progression or unacceptable toxicity. Patients then receive avelumab alone
      IV over 60 minutes on days 1 and 8. Cycles repeat every 21 days for up to 1 more year in the
      absence of disease progression or unacceptable toxicity.

      ARM B: Patients receive avelumab, gemcitabine hydrochloride, and carboplatin as in Arm A.

      After completion of study treatment, patients are followed up for 12 months.
    

Trial Arms

NameTypeDescriptionInterventions
Arm A (avelumab, gemcitabine, carboplatin, M6620)ExperimentalPatients receive avelumab IV over 60 minutes and gemcitabine hydrochloride IV over 30 minutes on days 1 and 8. Patients also receive carboplatin IV over 30 minutes on day 1 and berzosertib IV over 60 minutes on days 2 and 9. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive avelumab IV over 60 minutes on days 1 and 8 and berzosertib IV over 60 minutes on days 2 and 9. Cycles repeat every 21 days for up to 9 months in the absence of disease progression or unacceptable toxicity. Patients then receive avelumab alone IV over 60 minutes on days 1 and 8. Cycles repeat every 21 days for up to 1 more year in the absence of disease progression or unacceptable toxicity.
  • Avelumab
  • Berzosertib
  • Carboplatin
  • Gemcitabine Hydrochloride
Arm B (avelumab, gemcitabine, carboplatin)Active ComparatorPatients receive avelumab, gemcitabine, and carboplatin as in Arm A.
  • Avelumab
  • Carboplatin
  • Gemcitabine Hydrochloride

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must have histologically confirmed NSCLC of predominantly squamous cell
             histology, stage IV (American Joint Committee on Cancer [AJCC] 8th edition)

          -  Patients must have measurable disease, as defined by Response Evaluation Criteria in
             Solid Tumors (RECIST) version (v)1.1

          -  Patients must have tumor tissue available at time of enrollment, or be willing to
             undergo a biopsy for integrated biomarker studies

          -  Patients with a history of prior platinum-based systemic chemotherapy given as
             neoadjuvant, adjuvant, or consolidation therapy for early stage or loco-regionally
             advanced NSCLC are eligible, if therapy is completed one year prior to initiation of
             treatment. Patients must not have had prior systemic chemotherapy or immunotherapy for
             metastatic disease

          -  Patients with prior immunotherapy given as neoadjuvant, adjuvant, or consolidation
             therapy for early stage or loco-regionally advanced disease are eligible, if treatment
             is completed one year prior to initiation of treatment

          -  Patients must have Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
             (Karnofsky > 60%)

          -  Leukocytes >= 3,000/mcL

          -  Absolute neutrophil count > lower limit of normal (LLN)

          -  Platelets > LLN

          -  Total bilirubin =< institutional upper limit of normal (ULN)

          -  Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
             [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
             =< 3 x institutional ULN

          -  Creatinine =< institutional ULN OR glomerular filtration rate (GFR) >= 60 mL/min/1.73
             m^2 unless data exists supporting safe use at lower kidney function values, no lower
             than 30 mL/min/1.73 m^2

          -  Patients with human immunodeficiency virus (HIV) infection are eligible if they are on
             effective anti-retroviral therapy with undetectable viral load within 6 months,
             provided there is no expected drug-drug interaction

          -  Patients with evidence of chronic hepatitis B virus (HBV) infection are eligible if
             the HBV viral load is undetectable on suppressive therapy (if indicated), provided
             there is no expected drug-drug interaction

          -  Patients with a history of hepatitis C virus (HCV) infection are eligible if they have
             been treated and cured. For patients with HCV infection who are currently on
             treatment, they are eligible if they have an undetectable HCV viral load

          -  Patients with treated brain metastases are eligible if clinically stable, i.e., on
             stable doses of anti-convulsant therapy and/or stable doses of corticosteroids which
             are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid

          -  Patients with a prior or concurrent malignancy whose natural history or treatment does
             not have the potential to interfere with the safety or efficacy assessment of the
             investigational regimen are eligible for this trial

          -  Patients with known history or current symptoms of cardiac disease, or history of
             treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac
             function using the New York Heart Association Functional Classification. To be
             eligible for this trial, patients should be class 2B or better

          -  Patients must be willing to comply with birth control requirements: The effects of the
             agents in this study (or similar agents) on the developing human fetus are either
             unknown, or known to be teratogenic, embryotoxic, and fetotoxic in mice and rabbits.
             For this reason, women of child-bearing potential and men must agree to use adequate
             contraception (hormonal or barrier method of birth control; abstinence) prior to study
             entry, for the duration of study participation, and for 6 months after completing
             treatment administration. Should a woman become pregnant or suspect she is pregnant
             while she or her partner is participating in this study, she should inform her
             treating physician immediately. Men treated or enrolled on this protocol must also
             agree to avoid donating sperm for during the study period, and to use adequate
             contraception prior to the study, for the duration of study participation, and for 6
             months after completion completing treatment administration

          -  Patients must have the ability to understand and willingness to sign a written
             informed consent document. Participants with impaired decision-making capacity who
             have a legally-authorized representative and/or family member available will also be
             eligible

        Exclusion Criteria:

          -  Patients with severe intercurrent illness or comorbidity are not eligible

          -  Patients with contraindications to immunotherapy (e.g., solid organ transplant or
             active autoimmune disease requiring immunosuppressant therapy within 2 years of
             enrollment) are not eligible

          -  Patients with prior systemic chemotherapy for metastatic disease are not eligible

          -  Patients who are receiving any other investigational agents are not eligible

          -  Patients with a history of allergic reactions attributed to compounds of similar
             chemical or biologic composition to M6620, avelumab, gemcitabine, carboplatin, or
             other agents used in study are not eligible

          -  Patients with severe bone marrow depression or significant bleeding are not eligible

          -  Patients with psychiatric illness/social situations that would limit compliance with
             study requirements are not eligible

          -  M6620 is primarily metabolized by CYP3A4; therefore, concomitant administration with
             strong inhibitors of CYP3A4 (e.g. clarithromycin, itraconazole, ketoconazole, HCV and
             HIV protease inhibitors, nefazodone, posaconazole, telithromycin, voriconazole) or
             strong inducers of CYP3A4 (e.g. carbamazepine, rifampin, phenobarbital, phenytoin, St.
             John's wort) should be avoided. Because the lists of these agents are constantly
             changing, it is important to regularly consult a frequently-updated medical reference.
             As part of the enrollment/informed consent procedures, the patient will be counseled
             on the risk of interactions with other agents, and what to do if new medications need
             to be prescribed or if the patient is considering a new over-the-counter medicine or
             herbal product

          -  Pregnant women are excluded from this study because the agents in this study may have
             the potential for teratogenic or abortifacient effects. Because there is an unknown
             but potential risk for adverse events in nursing infants secondary to treatment of the
             mother with the study agents, breastfeeding should be discontinued if the mother is
             treated with the study agents M6620, avelumab, gemcitabine, or carboplatin

          -  M6620 should be used with caution in patients with clinical evidence of germline
             defects in their deoxyribonucleic acid (DNA) damage repair pathway (for example,
             patients with Li-Fraumeni syndrome or ataxia telangiectasia) due to a possible
             increase in the toxicity of DNA-damaging agents when paired with M6620

          -  Patients must not have received or be scheduled to receive radiation therapy within 7
             days or less from gemcitabine administration

          -  Current or prior use of immunosuppressive medication within 28 days before the first
             dose of avelumab, with the exceptions of intranasal and inhaled corticosteroids or
             systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of
             prednisone, or an equivalent corticosteroid

          -  Patients must not have received an allogeneic stem cell transplant

          -  Patients must not have active, uncontrolled infections or recently received active
             vaccinations
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Recommended phase 2 dose (RP2D) (Phase 1B)
Time Frame:Up to completion of cycle 1
Safety Issue:
Description:The RP2D will be the dose selected during Phase 1B.

Secondary Outcome Measures

Measure:PFS in the subset of patients with ATM-deficient squamous cell non-small cell lung cancer
Time Frame:From the date of randomization to time of progression or death, whichever occurs first, assessed up to 12 months post treatment
Safety Issue:
Description:Proportional hazards (Cox) regression will be used to estimate the hazard ratio. The hazard ratio will be estimated with a 95% confidence interval. The assumption of proportionality of hazards will be checked graphically and by the method of Therneau and Grambsch. If it is found that the assumption is violated, the log-rank test will be used to compare the product-limit estimates of the survival functions. PFS of the participants in the M6620 arm will be modeled as a function of total M6620 exposure using logistic regression, proportional hazards (Cox) regression and cumulative logit models, as appropriate.
Measure:Overall survival (OS)
Time Frame:Up to 12 months post treatment
Safety Issue:
Description:Proportional hazards (Cox) regression will be used to estimate the hazard ratio. The hazard ratio will be estimated with a 95% confidence interval. The assumption of proportionality of hazards will be checked graphically and by the method of Therneau and Grambsch. If it is found that the assumption is violated, the log-rank test will be used to compare the product-limit estimates of the survival functions. OS of the participants in the M6620 arm will be modeled as a function of total M6620 exposure using logistic regression, proportional hazards (Cox) regression and cumulative logit models, as appropriate.
Measure:Overall response (OR)
Time Frame:Up to 12 months post treatment
Safety Issue:
Description:Overall response will be analyzed by means of Fisher's exact test. Objective response of the participants in the M6620 arm will be modeled as a function of total M6620 exposure using logistic regression, proportional hazards (Cox) regression and cumulative logit models, as appropriate.
Measure:Worst grade of adverse events
Time Frame:Up to 12 months post treatment
Safety Issue:
Description:Adverse events will be tabulated according to Common Terminology Criteria for Adverse Events version 5.0 type, grade and relation to treatment. The worst grade of adverse event will be determined for each participant, and the distributions of worst grades will be compared between arms using a cumulative logit model. Worst grade of adverse event experienced of the participants in the M6620 arm will be modeled as a function of total M6620 exposure using logistic regression, proportional hazards (Cox) regression and cumulative logit models, as appropriate.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

July 21, 2020