Combination Treatment (Talazoparib Plus Avelumab) for Stage IV or Recurrent Non-Squamous Non-Small Cell Lung Cancer With STK11 Gene Mutation (A LUNG-MAP Treatment Trial)

• ClinicalTrials.gov Identifier: NCT04173507
• Recruitment Status: Active, not recruiting
• First Posted: November 22, 2019
• Results First Posted: January 9, 2023
• Last Update Posted: January 9, 2023
• Sponsor: Southwest Oncology Group
• Collaborator: National Cancer Institute (NCI)
• Information provided by (Responsible Party): Southwest Oncology Group

Tracking Information

• First Submitted Date: November 20, 2019
• First Posted Date: November 22, 2019
• Results First Submitted Date: October 18, 2022
• Results First Posted Date: January 9, 2023
• Last Update Posted Date: January 9, 2023
• Actual Study Start Date: February 14, 2020
• Actual Primary Completion Date: November 24, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 14, 2022)

• Objective Response Rate (ORR) [ Time Frame: From date of registration to progression or treatment discontinuation, up to 1 year and 9 months ]
  Percentage of participants with confirmed or unconfirmed, complete or partial response to treatment with talazoparib plus avelumab per Response Evaluation Criteria in Solid Tumors (RECIST 1.1) criteria. Complete Response (CR): Complete disappearance of all target and non-target lesions. No new lesions. No disease related symptoms. Any lymph nodes (whether target or non-target) must have reduction in short axis to < 1.0 cm. All disease must be assessed using the same technique as baseline. Partial Response (PR): Applies only to participants with at least one measurable lesion. Greater than or equal to 30% decrease under baseline of the sum of appropriate diameters of all target measurable lesions. No unequivocal progression of non-measurable disease. No new lesions. All target measurable lesions must be assessed using the same techniques as baseline.
• Disease Control Rate at 12 Weeks (DCR12) [ Time Frame: 12 weeks after registration ]
  Percentage of participants with a best response of Complete Response (CR), Partial Response (PR), Unconfirmed Partial Response (UPR), or Unconfirmed Complete Response (UCR) by/at the second disease assessment at 12 weeks after registration (+/- 2 weeks), or stable disease at 12 weeks after registration (+/- 2 weeks). Participants with missing or delayed disease assessment at 12 weeks (+/- 2 weeks), at or before the disease assessment at 20 weeks (+/- 2 weeks) with documented lack of progression (CR, PR, UPR, UCR, or stable) were coded as having disease control at 12 weeks. Participants not known to have disease control at 12 weeks who have at least 12 weeks of follow-up were coded as not having disease control at 12 weeks.

Original Primary Outcome Measures (submitted: November 20, 2019)

• Best objective response rate (ORR) [ Time Frame: Up to 3 years ]
  Will be assessed by complete response (CR), unconfirmed CR (UCR), partial response (PR), and unconfirmed PR (UPR).
• Disease control rate [ Time Frame: At 12 weeks after registration ]
  Will be defined as a best response of CR, PR, UPR, or UCR by/at the second disease assessment at 12 weeks after registration (+/- 2 weeks), or stable disease at 12 weeks after registration (+/- 2 weeks).

Current Secondary Outcome Measures (submitted: December 14, 2022)

• Investigator-Assessed Progression-Free Survival (IA-PFS) [ Time Frame: From date of registration to a maximum of 3 years or death ]
  From date of sub-study registration to date of first documentation of progression assessed by local review or symptomatic deterioration, or death due to any cause. Participants last known to be alive without report of progression are censored at date of last disease assessment. For participants with a missing scan (or consecutive missing scans) whose subsequent scan determines progression, the expected date of the first missing scan (as defined by the disease assessment schedule) is used as the date of progression. Progression is defined as: 20% increase in the sum of appropriate diameters of target lesions and absolute increase of at least 0.5 cm, or unequivocal progression of non-measurable disease, or appearance of any new lesion/site, or death from disease without prior documentation of progression or symptomatic deterioration. Symptomatic deterioration: Global deterioration of health status requiring discontinuation of treatment without objective evidence of progression.
• Overall Survival (OS) [ Time Frame: From date of registration to a maximum of 3 years or death ]
  From date of sub-study registration to date of death due to any cause. Participants last known to be alive are censored at date of last contact.
• Duration of Response (DOR) [ Time Frame: From date of registration to a maximum of 3 years or death ]
  From date of first response to first progression assessed by local review or symptomatic deterioration, or death among patients with a response (CR or PR). Those last known to be alive without progression are censored at date of last disease assessment. For those with a missing scan whose next scan shows progression, expected date of the first missing scan is used as progression date. Complete Response (CR): Disappearance of all target and non-target lesions. No new lesions or disease related symptoms. Lymph nodes must have reduction in short axis to < 1.0cm. Assessed using same technique as baseline. Partial Response (PR): At least 30% decrease under baseline of the sum of appropriate diameters of all target measurable lesions. No unequivocal progression of non-measurable disease. No new lesions. Assessed using same technique as baseline. Symptomatic deterioration: Global deterioration of health status requiring discontinuation of treatment w/o objective evidence of progression.
• Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs [ Time Frame: Duration of treatment and follow up until death or 3 years post registration ]
  Only adverse events that are possibly, probably or definitely related to study drug are reported. CTCAE Version 5.0 was used for routine toxicity reporting and serious adverse events (SAEs).

Original Secondary Outcome Measures (submitted: November 20, 2019)

• Frequency and severity of toxicities [ Time Frame: Up to 3 years ]
  Will utilize the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0.
• Progression free survival [ Time Frame: From date of sub-study registration to date of first documentation of progression assessed by local review, central review, symptomatic deterioration, or death due to any cause, assessed up to 3 years ]
  Binary proportions and associated confidence intervals will be calculated. The method of Kaplan-Meier will be used to estimate survival distributions and the Brookmeyer-Crowley method will be used to estimate confidence intervals around medians.
• Overall survival [ Time Frame: Up to 3 years ]
  Binary proportions and associated confidence intervals will be calculated. The method of Kaplan-Meier will be used to estimate survival distributions and the Brookmeyer-Crowley method will be used to estimate confidence intervals around medians.
• Duration of response [ Time Frame: From date of first documentation of response (CR or PR) to date of first documentation of progression assessed by local review or symptomatic deterioration, or death due to any cause among patients who achieve a response (CR or PR), up to 3 years ]
  Binary proportions and associated confidence intervals will be calculated. The method of Kaplan-Meier will be used to estimate survival distributions and the Brookmeyer-Crowley method will be used to estimate confidence intervals around medians.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Combination Treatment (Talazoparib Plus Avelumab) for Stage IV or Recurrent Non-Squamous Non-Small Cell Lung Cancer With STK11 Gene Mutation (A LUNG-MAP Treatment Trial)
• Official Title: A Phase II Study of Talazoparib Plus Avelumab in Patients With Stage IV or Recurrent Non-Squamous Non-Small Cell Lung Cancer Bearing Pathogenic STK11 Genomic Alterations (LUNG-MAP Sub-Study)
• Brief Summary: This phase II LUNG-MAP treatment trial studies how well combination treatment (talazoparib plus avelumab) works in treating patients with non-squamous non-small cell lung cancer that has an STK11 gene mutation and has come back (recurrent) or is stage IV. Talazoparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. 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. Immunotherapy drugs given as single therapies or in combination with chemotherapy do not appear to work as well in lung cancer cells with mutations in the STK11 gene versus those that do not have the mutation. Adding the medicine talazoparib to the immunotherapy drug avelumab may work better in treating lung cancers that have an STK11 gene mutation.

Detailed Description

PRIMARY OBJECTIVES:

I. To evaluate the objective response rate (ORR) (confirmed and unconfirmed, complete and partial) with talazoparib plus avelumab in patients with stage IV or recurrent non-squamous non-small cell lung cancer bearing pathogenic STK11 genomic alterations that were previously-treated with anti-PD-1/PD-L1 therapy and platinum-based chemotherapy.

II. To evaluate disease control rate at 12 weeks (DCR12) after registration.

SECONDARY OBJECTIVES:

I. To evaluate investigator assessed progression-free survival (IA-PFS). II. To evaluate overall survival (OS). III. To evaluate duration of response (DOR) among responders. IV. To evaluate the frequency and severity of toxicities.

TRANSLATIONAL MEDICINE OBJECTIVES:

I. To collect, process, and bank cell-free deoxyribonucleic acid (DNA) (cfDNA) at baseline, cycle 3 day 1, progression, and end of treatment for future development of a proposal to evaluate comprehensive next-generation sequencing of circulating tumor DNA (ctDNA) and examine molecular mechanisms of resistance to talazoparib and avelumab.

II. To establish a tissue/blood repository from patients with refractory non-small cell lung cancer (NSCLC).

III. To evaluate clinical outcomes (ORR, IA-PFS, OS) in patients with concurrent somatic mutations in KEAP1 detected on the Foundation Medicine Inc. (FMI) panel from the LUNGMAP screening protocol.

IV. To evaluate clinical outcomes (ORR, IA-PFS, OS) in patients with concurrent mutations in ATM or other DNA damage response genes detected on the FMI panel from the LUNGMAP screening protocol.

V. To evaluate the association between tumor mutational burden (TMB) measured on the FMI panel from the LUNGMAP screening protocol and clinical outcomes (ORR, IA-PFS, OS).

OUTLINE:

Patients receive talazoparib orally (PO) daily and avelumab intravenously (IV) over 60 minutes on days 1 and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up until death or 3 years after sub-study registration.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Advanced Lung Non-Squamous Non-Small Cell Carcinoma
• Recurrent Lung Non-Squamous Non-Small Cell Carcinoma
• Stage IV Lung Cancer AJCC v8
• Stage IVA Lung Cancer AJCC v8
• Stage IVB Lung Cancer AJCC v8

Intervention

• Drug: Avelumab
  Given IV
  Other Names:

  • Bavencio
  • MSB-0010718C
  • MSB0010718C
• Drug: Talazoparib
  Given PO
  Other Names:

  • BMN 673
  • BMN-673
• Drug: Talazoparib Tosylate
  Given PO
  Other Name: Talzenna

Study Arms

Experimental: Treatment (talazoparib, avelumab)

Patients receive talazoparib PO daily and avelumab IV over 60 minutes on days 1 and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Interventions:

• Drug: Avelumab
• Drug: Talazoparib
• Drug: Talazoparib Tosylate

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: September 21, 2021): 47
• Original Estimated Enrollment (submitted: November 20, 2019): 44
• Estimated Study Completion Date: February 1, 2023
• Actual Primary Completion Date: November 24, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Patients must be assigned to S1900C. Assignment to S1900C is determined by the LUNGMAP protocol genomic profiling using the FoundationOne assay. Biomarker eligibility for S1900C is based on the identification of a pathogenic somatic mutation in STK11 or STK11 bi-allelic loss on tumor
• Patients must have histologically or cytologically confirmed stage IV or recurrent non-squamous, mixed squamous/non-squamous (e.g., adeno-squamous carcinoma), or non-small cell lung cancer not otherwise specified (NSCLC NOS). Patients with pure squamous cell carcinoma are not eligible
• Patients with evidence of chronic hepatitis B virus (HBV) infection must have undetectable HBV viral load on suppressive therapy within 28 days prior to sub-study registration
• Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. Patients with HCV infection who are currently on treatment must have an undetectable HCV viral load within 28 days prior to sub-study registration
• Patients with known human immunodeficiency virus (HIV) infection are eligible, provided they are on effective anti-retroviral therapy and have undetectable viral load at their most recent viral load test and within 6 months prior to sub-study registration

• Patients must have received at least one line of anti-PD-1 or anti-PD-L1 therapy for stage III, IV or recurrent disease. Any number of additional, non-platinum-based chemotherapy or targeted therapy regimens for recurrent or metastatic disease are allowed

  • Patients may not have received more than one line of anti-PD-1 or anti-PD-L1 therapy in the Stage IV or recurrent setting. Anti-PD-1 or anti-PD-L1 therapy may have been given alone or in combination with platinum-based chemotherapy, an anti-CTLA4 therapy, or other immune-modulatory therapy. Patients must have experienced disease progression > 42 days following initiation (cycle 1 day 1) of the anti-PD-1 or anti-PD-L1 containing regimen
  • Patients who did not receive anti-PD-1 or anti-PD-L1 therapy in combination with platinum-based chemotherapy, must have also received prior platinum-based chemotherapy and experienced disease progression > 42 days following initiation (cycle 1 day 1) of platinum based chemotherapy
  • Patients who received anti-PD-1 or anti-PD-L1 therapy following concurrent chemoradiation for stage III disease as their only line of anti-PD-1 or anti-PD-L1 therapy, are eligible if they experienced disease progression less than (<) 365 days from the date of initiation of anti-PD-1 or anti-PD-L1 therapy
• Patients who received prior adjuvant platinum-based therapy post-surgical resection for stage I-III disease (i.e. the patient has not received platinum-based chemotherapy for Stage IV or recurrent disease) must have had disease progression during or after platinum-based chemotherapy that occurred less than (<) 365 days from the last date that the patient received that therapy
• Patients must be able to swallow capsules whole
• Patients must not have had prior exposure to any agent with a PARP inhibitor (e.g., veliparib, olaparib, rucaparib, niraparib, talazoparib) as its primary pharmacology
• Patients must not be taking, nor plan to take while on protocol treatment strong P-glycoprotein (P-gp) inhibitors (e.g. dronedarone, quinidine, ranolazine, itraconazole, ketoconazole), P-gp inducers (rifampin, ritonavir, tipranavir), or strong breast cancer resistance protein (BCRP) inhibitors (e.g. elacridar)
• Patients must have progressed following their most recent line of therapy
• Patients must not have received any prior systemic therapy (systemic chemotherapy, immunotherapy or investigational drug) within 21 days prior to sub-study registration. Patients must have recovered (=< grade 1) from any side effects of prior therapy. Patients must not have received any radiation therapy within 14 days prior to sub-study registration
• Patients must not be planning to receive any concurrent chemotherapy, immunotherapy, biologic or hormonal therapy for cancer treatment while receiving treatment on this study. Concurrent use of hormones for non-cancer-related conditions (e.g., insulin for diabetes and hormone replacement therapy) is acceptable
• Patients must have measurable disease documented by computed tomography (CT) or magnetic resonance imaging (MRI). The CT from a combined positron emission tomography (PET)/CT may be used to document only non-measurable disease unless it is of diagnostic quality. Measurable disease must be assessed within 28 days prior to sub-study registration. Pleural effusions, ascites and laboratory parameters are not acceptable as the only evidence of disease. Non-measurable disease must be assessed within 42 days prior to sub-study registration. All disease must be assessed and documented on the Baseline Tumor Assessment Form. Patients whose only measurable disease is within a previous radiation therapy port must demonstrate clearly progressive disease (in the opinion of the treating investigator) prior to sub-study registration. CT and MRI scans must be submitted for central review via Transfer of Images and Data (TRIAD)
• Patients must have a CT or MRI scan of the brain to evaluate for central nervous system (CNS) disease within 42 days prior to sub-study registration. Patient must not have leptomeningeal disease, spinal cord compression or brain metastases unless: (1) metastases have been locally treated and have remained clinically controlled and asymptomatic for at least 14 days following treatment, and prior to sub-study registration, AND (2) patient has no residual neurological dysfunction and has been off corticosteroids for at least 24 hours prior to sub-study registration
• Patient must not have had a major surgery within 14 days prior to sub-study registration. Patient must have fully recovered from the effects of prior surgery in the opinion of the treating investigator
• Serum bilirubin =< institutional upper limit of normal (IULN) (within 28 days prior to sub-study registration). For patients with liver metastases, bilirubin must be =< 5 x IULN
• Either alanine aminotransferase (ALT) or aspartate aminotransferase (AST) =< 2 x IULN within 28 days prior to sub-study registration (if both ALT and AST are done, both must be =< 2 IULN). For patients with liver metastases, either ALT or AST must be =< 5 x IULN (if both ALT and AST are done, both must be =< 5 x IULN)
• Patients must have a serum creatinine =< the IULN or calculated creatinine clearance >= 50 mL/min using the following Cockcroft-Gault formula. This specimen must have been drawn and processed within 28 days prior to sub-study registration
• Patients must have Zubrod performance status 0-1 documented within 28 days prior to sub-study registration
• Patients must not have any grade III/IV cardiac disease as defined by the New York Heart Association Criteria (i.e., patients with cardiac disease resulting in marked limitation of physical activity or resulting in inability to carry on any physical activity without discomfort), unstable angina pectoris, and myocardial infarction within 6 months, or serious uncontrolled cardiac arrhythmia
• Pre-study history and physical exam must be obtained within 28 days prior to sub-study registration
• No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for five years
• Absolute neutrophil count (ANC) >= 1,500/mcl (obtained within 28 days prior to sub-study registration). Patients must be transfusion independent (i.e., no blood product transfusions for a period of at least 14 days prior to sub-study registration)
• Platelet count >= 100,000 mcl (obtained within 28 days prior to sub-study registration). Patients must be transfusion independent (i.e., no blood product transfusions for a period of at least 14 days prior to sub-study registration)
• Hemoglobin >= 9 g/dL (obtained within 28 days prior to sub-study registration). Patients must be transfusion independent (i.e., no blood product transfusions for a period of at least 14 days prior to sub-study registration)
• Patients must agree to have blood specimens submitted for circulating tumor DNA (ctDNA)
• Patients must also be offered participation in banking and in the correlative studies for collection and future use of specimens

Exclusion Criteria:

• Patients must not be pregnant or nursing. Women/men of reproductive potential must have agreed to use an effective contraceptive method. A woman is considered to be of "reproductive potential" if she has had menses at any time in the preceding 12 consecutive months. In addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation. However, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures
• Patients must not have a history of prior organ transplantation, including allogeneic stem-cell transplantation
• Patients must not have received systemic treatment with corticosteroids (> 10 mg daily prednisone or equivalent) or other immunosuppressive medications within 7 days prior to sub-study registration. Inhaled or topical steroids, and adrenal replacement doses =< 10 mg daily prednisone or equivalent are permitted in the absence of active autoimmune disease
• Patients must not have active autoimmune disease that requires systemic steroids (equivalent of > 10 mg of prednisone) or immunosuppressive agents within 7 days prior to sub-study registration (for example disease-modifying anti-rheumatic drugs). Exceptions include: patients with controlled type 1 diabetes mellitus, controlled hypo- or hyperthyroidism, vitiligo, resolved childhood asthma/atopy, or psoriasis not requiring immunosuppressive therapy
• Patients must not have any impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of talazoparib (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection, or active peptic ulcer disease). Patients must not have active small or large intestine inflammation such as Crohn's disease or ulcerative colitis within 12 months prior to sub-study registration
• Patients must not have known prior or suspected hypersensitivity to monoclonal antibodies (grade >= 3)

• Patients must not have any history of anaphylaxis or uncontrolled asthma. Uncontrolled asthma is defined as a patient having any one of the following criteria:

  • Poor symptom control: Asthma Control Questionnaire (ACQ) consistently > 1.5 or Asthma Control Test Questionnaire (ACT) < 20 (or "not well controlled" by National Asthma Education and Prevention Program [NAEPP] or Global Initiative for Asthma [GINA] guidelines over the 3 months or evaluation)
  • Frequent severe exacerbations: 2 or more bursts of systemic corticosteroids (CSs) (> 3 days each) in the previous year
  • Serious exacerbations: at least one hospitalization, intensive care unit stay or mechanical ventilation in the previous year
  • Airflow limitation: Forced expiratory volume in 1 second (FEV1) < 80% predicted (in the presence of reduced FEV1/forced vital capacity [FVC] defined as less than the normal lower limit) following a withhold of both short- and long-acting bronchodilators
• Patients must not have experienced any immune related adverse event, including pneumonitis that led to permanent discontinuation of prior immunotherapy and/or required prolonged high dose of steroids
• Patients must not have evidence of active infection requiring systemic therapy
• Patients must not have received any live attenuated vaccinations within 28 days prior to sub-study registration

Sex/Gender

• Sexes Eligible for Study: All

• Ages: Child, Adult, Older Adult
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT04173507
• Other Study ID Numbers: S1900C; NCI-2019-07142 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); S1900C ( Other Identifier: SWOG ); S1900C ( Other Identifier: CTEP ); U10CA180888 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: Not Provided

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Southwest Oncology Group
• Original Responsible Party: Same as current
• Current Study Sponsor: Southwest Oncology Group
• Original Study Sponsor: Same as current
• Collaborators: National Cancer Institute (NCI)

Investigators

• Principal Investigator: Ferdinandos Skoulidis; Southwest Oncology Group

• PRS Account: Southwest Oncology Group
• Verification Date: December 2022