Lung-MAP: Talazoparib in Treating Patients With HRRD Positive Recurrent Stage IV Squamous Cell Lung Cancer

Study Overview
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Brief Summary
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This phase II trial studies how well talazoparib works in treating patients with homologous recombination repair deficiency (HRRD) positive stage IV squamous cell lung cancer that has come back after previous treatment. Talazoparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed Description
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PRIMARY OBJECTIVES: I. To evaluate the overall response rate (ORR) (confirmed and unconfirmed, complete and partial) with talazoparib (BMN 673) in HRRD Medivation (MDVN)-positive patients. SECONDARY OBJECTIVES: I. To evaluate investigator assessed progression-free survival (IA-PFS) and overall survival (OS) associated with therapy in HRRD MDVN-positive patients. II. To evaluate ORR, IA-PFS, and OS in HRRD Foundation Medicine, Inc. (FMI)-positive patients. III. To evaluate ORR in HRRD MDVN-negative/HRRD FMI-positive patients. IV. To evaluate the frequency and severity of toxicities associated with talazoparib (BMN 673) in HRRD FMI-positive patients. TERTIARY OBJECTIVES: I. To assess if the homologous recombination deficiency (HRD) score is associated with clinical outcomes (response, PFS, OS) in HRRD FMI-positive patients treated with talazoparib (BMN 673). II. To assess if the level of PARP protein expression determined by immunohistochemistry is associated with clinical outcomes (response, PFS, OS) in HRRD FMI-positive patients treated with talazoparib (BMN 673). III. To characterize pharmacokinetic properties of talazoparib (BMN 673). OUTLINE: Patients receive talazoparib orally (PO) once daily (QD) on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 3 months for 1 year, every 6 months for 2 years, and at the end of year 3.

Official Title
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A Phase II Study of Talazoparib (BMN 673) in Patients With Homologous Recombination Repair Deficiency Positive Stage IV Squamous Cell Lung Cancer (Lung-Map Sub-Study)

Conditions
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ATM Gene Mutation, ATR Gene Mutation, BARD1 Gene Mutation, BRCA1 Gene Mutation, BRCA2 Gene Mutation, BRIP1 Gene Mutation, CHEK1 Gene Mutation, CHEK2 Gene Mutation, FANCA Gene Mutation, FANCC Gene Mutation, FANCD2 Gene Mutation, FANCF Gene Mutation, FANCM Gene Mutation, NBN Gene Mutation, PALB2 Gene Mutation, RAD51 Gene Mutation, RAD51B Gene Mutation, RAD54L Gene Mutation, Recurrent Squamous Cell Lung Carcinoma, RPA1 Gene Mutation, Stage IV Squamous Cell Lung Carcinoma AJCC v7

Intervention / Treatment
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* Other: Laboratory Biomarker Analysis
* Other: Pharmacological Study
* Drug: Talazoparib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must meet all SCREENING/PRE-SCREENING and SUB-STUDY REGISTRATION COMMON ELIGIBILITY CRITERIA as specified in S1400: Phase II/III Biomarker-Driven Master Protocol for Previously Treated Squamous Cell Lung Cancer (Lung-Map) Patients must be assigned to S1400G; S1400G biomarker eligibility defined as homologous recombination repair deficiency (HRRD) positive is as follows Biomarker-positive group HRRD by FMI Homologous recombination repair deficiency by Foundation Medicine Inc., criteria Alteration type Truncating mutation, frameshift deletions, indels missense and nonsense mutations predicted to have functional consequence in any of the specified genes Eligible alteration Mutation in any one of the following critical HRR pathway genes: ATM, ATR, BARD1, BRCA1, BRCA2, BRIP1, CHEK1, CHEK2, FANCA, FANCC, FANCD2, FANCF, FANCM, NBN (NBS1), PALB2, RAD51, RAD51B (RAD51L1), RAD54L, RPA1 Patients must not have had prior exposure to any agent with a PARP inhibitor (e.g., veliparib, olaparib, rucaparib, niraparib, talazoparib [BMN 673]) as its primary pharmacology Patients must have achieved stable disease, a partial response, or a complete response at their first disease assessment after initiating first-line platinum-based chemotherapy; patients determined to have progressed (in the opinion of the treating physician) at their first disease assessment are not eligible Patients may not have any impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of talazoparib (BMN 673) (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 of sub-study registration) Patients must be able to take oral medications; patients must be able to swallow capsules whole without crushing or altering them in any way Patients must not be taking, nor plan to take while on protocol treatment strong P-glycoprotein (P-gp) inhibitors, P-gp inducers, or breast cancer resistance protein (BCRP) inhibitors; the language ?P-gp or BCRP inhibitors or inducers? is reworded to ?strong P-gp inhibitors, P-gp inducers, or BCRP inhibitors? for consistency with the investigator brochure Patients must agree to have blood specimens submitted for pharmacokinetic analysis
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (talazoparib)<br>Patients receive talazoparib PO QD on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. | Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Pharmacological Study<br>* Correlative studies<br>Drug: Talazoparib<br>* Given PO<br>* Other names: BMN-673;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate Assessed by Response Evaluation Criteria in Solid Tumors 1.1 in HRRD-positive (MDVN) Participants | The percentage of participants with confirmed and unconfirmed, partial response and complete response to treatment with talazoparib per Response Evaluation Criteria in Solid Tumors Criteria (RECIST 1.1). Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI or CT: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR Analysis was performed using a more restricted definition of homologous recombination repair deficiency (HRRD)-positivity (Medivation [MDVN] criteria; defined by alterations in ATM/ATR/BRCA1/BRCA2/PALB2 genes). With 40 HRRD subset positive patients, overall response rate can be estimated within 13% with 95% confidence. | Up to 3 years post sub-study registration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Investigator-assessed Progression-free Survival (IA-PFS) in HRRD-positive (MDVN) Participants | 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 were censored at date of last disease assessment. Analysis was performed using a more restricted definition of homologous recombination repair deficiency (HRRD)-positivity (Medivation [MDVN] criteria; defined by alterations in ATM/ATR/BRCA1/BRCA2/PALB2 genes). | Up to 3 years post sub-study registration | 
| Overall Survival (OS) in HRRD-positive (MDVN) Participants | From date of sub-study registration to date of death due to any cause. Participants last known to be alive were censored at date of last contact. Analysis was performed using a more restricted definition of homologous recombination repair deficiency (HRRD)-positivity (Medivation [MDVN] criteria; defined by alterations in ATM/ATR/BRCA1/BRCA2/PALB2 genes). | Up to 3 years post sub-study registration | 
| Overall Response Rate Assessed by Response Evaluation Criteria in Solid Tumors 1.1 in HRRD-positive (FMI) Participants | The percentage of participants with confirmed and unconfirmed, partial response and complete response to treatment with talazoparib per Response Evaluation Criteria in Solid Tumors Criteria (RECIST 1.1). Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI or CT: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR Analysis was performed using a broader definition of homologous recombination repair deficiency (HRRD)-positivity (Foundation Medicine Inc. [FMI] criteria; defined by alterations in ATM/ATR/BARD1/BRCA1/BRCA2/BRIP1/CHEK1/CHEK2/FANCA/FANCC/FANCD2/FANCF/FANCM/NBN(NBS1)/PALB2/RAD51/RAD51B(RAD51L1)/RAD54L/RPA1 genes). | 3 years post sub-study registration | 
| Investigator-assessed Progression Free Survival (IA-PFS) FEP in HRRD-positive (FMI) Participants | 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 were censored at date of last disease assessment. Analysis was performed using a broader definition of homologous recombination repair deficiency (HRRD)-positivity (Foundation Medicine Inc. [FMI] criteria; defined by alterations in ATM/ATR/BARD1/BRCA1/BRCA2/BRIP1/CHEK1/CHEK2/FANCA/FANCC/FANCD2/FANCF/FANCM/NBN(NBS1)/PALB2/RAD51/RAD51B(RAD51L1)/RAD54L/RPA1 genes). | 3 years post sub-study registration | 
| Overall Survival (OS) in HRRD-positive (FMI) Participants | From date of sub-study registration to date of death due to any cause. Participants last known to be alive were censored at date of last contact. Analysis was performed using a broad definition of homologous recombination repair deficiency (HRRD)-positivity (Foundation Medicine Inc. [FMI] criteria; defined by alterations in ATM/ATR/BARD1/BRCA1/BRCA2/BRIP1/CHEK1/CHEK2/FANCA/FANCC/FANCD2/FANCF/FANCM/NBN(NBS1)/PALB2/RAD51/RAD51B(RAD51L1)/RAD54L/RPA1 genes). | 3 years post sub-study registration | 
| Duration of Response in HRRD-positive (FMI) Participants | From date of documentation of response (complete or partial) to date of first documentation of progression assessed by local review or symptomatic deterioration or death due to any cause among participants who achieve a complete or partial response. | Up to 3 years | 
| Overall Response Rate Assessed by Response Evaluation Criteria in Solid Tumors 1.1 in HRRD-negative Per MDVN But HRRD-positive Per FMI Participants | The percentage of participants with confirmed and unconfirmed, partial response and complete response to treatment with talazoparib per Response Evaluation Criteria in Solid Tumors Criteria (RECIST 1.1). Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI or CT: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR Analysis was performed on participants that meet a broader definition of homologous recombination repair deficiency (HRRD)-positivity (Foundation Medicine Inc.) but not the stricter definition set by MDVN. [FMI] criteria; defined by alterations in ATM/ATR/BARD1/BRCA1/BRCA2/BRIP1/CHEK1/CHEK2/FANCA/FANCC/FANCD2/FANCF/FANCM/NBN(NBS1)/PALB2/RAD51/RAD51B(RAD51L1)/RAD54L/RPA1 genes). | 3 years post sub-study registration | 
| Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Adverse Events (AEs) are reported by CTCAE Version 4.0. Only adverse events that are possibly, probably or definitely related to study drug are reported. | Duration of treatment and follow up until death or 3 years post registration |