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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

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ClinicalTrials.gov Identifier: NCT04216316
Recruitment Status : Recruiting
First Posted : January 2, 2020
Last Update Posted : July 22, 2020
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Lung Non-Small Cell Squamous Carcinoma Stage IV Lung Cancer AJCC v8 Drug: Avelumab Drug: Berzosertib Drug: Carboplatin Drug: Gemcitabine Hydrochloride Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 106 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : June 1, 2020
Estimated Primary Completion Date : August 15, 2021
Estimated Study Completion Date : August 15, 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Arm A (avelumab, gemcitabine, carboplatin, M6620)
Patients 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.
Drug: Avelumab
Given IV
Other Names:
  • Bavencio
  • MSB-0010718C
  • MSB0010718C

Drug: Berzosertib
Given IV
Other Names:
  • 2-Pyrazinamine, 3-(3-(4-((Methylamino)methyl)phenyl)-5-isoxazolyl)-5-(4-((1-methylethyl)sulfonyl)phenyl)-
  • M 6620
  • M6620
  • VX 970
  • VX-970
  • VX970

Drug: Carboplatin
Given IV
Other Names:
  • Blastocarb
  • Carboplat
  • Carboplatin Hexal
  • Carboplatino
  • Carboplatinum
  • Carbosin
  • Carbosol
  • Carbotec
  • CBDCA
  • Displata
  • Ercar
  • JM-8
  • Nealorin
  • Novoplatinum
  • Paraplatin
  • Paraplatin AQ
  • Paraplatine
  • Platinwas
  • Ribocarbo

Drug: Gemcitabine Hydrochloride
Given IV
Other Names:
  • dFdCyd
  • Difluorodeoxycytidine Hydrochloride
  • FF 10832
  • FF-10832
  • FF10832
  • Gemcitabine HCI
  • Gemzar
  • LY-188011
  • LY188011

Active Comparator: Arm B (avelumab, gemcitabine, carboplatin)
Patients receive avelumab, gemcitabine, and carboplatin as in Arm A.
Drug: Avelumab
Given IV
Other Names:
  • Bavencio
  • MSB-0010718C
  • MSB0010718C

Drug: Carboplatin
Given IV
Other Names:
  • Blastocarb
  • Carboplat
  • Carboplatin Hexal
  • Carboplatino
  • Carboplatinum
  • Carbosin
  • Carbosol
  • Carbotec
  • CBDCA
  • Displata
  • Ercar
  • JM-8
  • Nealorin
  • Novoplatinum
  • Paraplatin
  • Paraplatin AQ
  • Paraplatine
  • Platinwas
  • Ribocarbo

Drug: Gemcitabine Hydrochloride
Given IV
Other Names:
  • dFdCyd
  • Difluorodeoxycytidine Hydrochloride
  • FF 10832
  • FF-10832
  • FF10832
  • Gemcitabine HCI
  • Gemzar
  • LY-188011
  • LY188011




Primary Outcome Measures :
  1. Recommended phase 2 dose (RP2D) (Phase 1B) [ Time Frame: Up to completion of cycle 1 ]
    The RP2D will be the dose selected during Phase 1B.

  2. Progression-free survival (PFS) (Phase 2) [ Time Frame: From the date of randomization to time of progression or death, whichever occurs first, assessed up to 12 months post treatment ]
    Proportional hazards (Cox) regression will be used to estimate the hazard ratio and the primary null hypothesis, that PFS is identical between arms, will be tested by a one-sided likelihood ratio test at alpha = 0.10. 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.


Secondary Outcome Measures :
  1. 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 ]
    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.

  2. Overall survival (OS) [ Time Frame: Up to 12 months post treatment ]
    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.

  3. Overall response (OR) [ Time Frame: Up to 12 months post treatment ]
    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.

  4. Worst grade of adverse events [ Time Frame: Up to 12 months post treatment ]
    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.


Other Outcome Measures:
  1. Determination if features of whole exome and ribonucleic acid (RNA) sequencing are predictive OR, OS, or PFS [ Time Frame: Up to 12 months post treatment ]
    Sparse modeling (e.g., the lasso) will be used to determine if any features of whole exome and RNA sequencing are predictive of OR, OS or PFS.

  2. ATM assay [ Time Frame: Up to 12 months post treatment ]
    Proportional hazards (Cox) regression will be used to assess the relationship between the ATM assay and OS and PFS.

  3. Inflammation-associated gene signatures [ Time Frame: Up to 12 months post treatment ]
    Logistic regression and proportional hazards (Cox) regression will be used to explore the relationship between inflammation-associated gene signatures and OR, OS, and PFS.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04216316


Locations
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United States, Pennsylvania
University of Pittsburgh Cancer Institute (UPCI) Recruiting
Pittsburgh, Pennsylvania, United States, 15232
Contact: Site Public Contact    412-647-8073      
Principal Investigator: Liza C. Villaruz         
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Liza C Villaruz University of Pittsburgh Cancer Institute LAO
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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT04216316    
Other Study ID Numbers: NCI-2019-08660
NCI-2019-08660 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
10313 ( Other Identifier: University of Pittsburgh Cancer Institute LAO )
10313 ( Other Identifier: CTEP )
UM1CA186690 ( U.S. NIH Grant/Contract )
First Posted: January 2, 2020    Key Record Dates
Last Update Posted: July 22, 2020
Last Verified: July 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.
URL: https://grants.nih.gov/policy/sharing.htm

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Lung Neoplasms
Carcinoma, Squamous Cell
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms, Squamous Cell
Gemcitabine
Carboplatin
Antibodies, Monoclonal
Antineoplastic Agents
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs