Deleterious BRCA1 Gene Mutation, Deleterious BRCA2 Gene Mutation, Loss of Heterozygosity, Lung Non-Small Cell Squamous Carcinoma, Recurrent Large Cell Lung Carcinoma, Recurrent Lung Adenocarcinoma, Recurrent Lung Non-Small Cell Carcinoma, Recurrent Non-Squamous Non-Small Cell Lung Carcinoma, Stage IVA Lung Cancer AJCC v8, Stage IVB Lung Cancer AJCC v8, Stage IV Lung Cancer AJCC v8
Conditions
Brief summary
This phase II Lung-MAP trial studies how well rucaparib works in treating patients with genomic loss of heterozygosity (LOH) high and/or deleterious BRCA1/2 mutation stage IV non-small cell lung cancer or that has come back. Rucaparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
Detailed description
PRIMARY OBJECTIVES: I. To evaluate the overall response rate (ORR) (confirmed and unconfirmed, complete and partial) associated with rucaparib in patients with genomic LOH high and/or deleterious BRCA1/2 mutations within: Cohort 1: Patients with squamous cell histology or mixed histology with a squamous component; Cohort 2: Patients with non-squamous histology (adenocarcinoma, large cell, or non-small cell lung cancer \[NSCLC\] not otherwise specified \[NOS\]). SECONDARY OBJECTIVES: I. To evaluate investigator assessed progression-free survival (IA-PFS) and overall survival (OS) associated with rucaparib within each cohort. II. To evaluate duration of response among responders within each cohort. III. To evaluate the frequency and severity of toxicities associated with rucaparib among all patients enrolled on the study (combining cohorts). TRANSLATIOAL MEDICINE OBJECTIVES: I. To evaluate the association between alterations in deoxyribonucleic acid (DNA) repair genes and response by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. II. To perform comprehensive next-generation sequencing of circulating tumor DNA (ctDNA) at baseline in all patients to assess its clinical utility in comparison to tumor tissue biomarker profiles. III. To establish a tissue/blood repository from patients with refractory non-small cell lung cancer (NSCLC). OUTLINE: Patients receive rucaparib orally (PO) twice daily (BID) 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, and then every 6 months for up to 3 years.
Interventions
DRUGRucaparib
Given PO
Sponsors
National Cancer Institute (NCI)
SWOG Cancer Research Network
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
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 S1900A. S1900A biomarker eligibility defined as LOH high and/or deleterious BRCA1/2 mutation is as follows using the Foundation Medicine Inc (FMI) tissue- assay: * LOH; alteration type: loss of heterozygosity (LOH); eligible alteration: Genomic LOH \>= 21% * BRCA; alteration type: homologous recombination deficiency (HRD); eligible alteration: Deleterious mutations in BRCA1 or BRCA2 * Patients must not have had prior treatment with any PARP inhibitor, including rucaparib, talazoparib, veliparib, olaparib, or niraparib. For information and a list of PARP inhibitors, please consult the S1900A ? Poly Polymerase Inhibitors, Scott et al., 2015 JCO ref from the link on the S1900A protocol abstract page of the SWOG (http://swog.org) or CTSU (https://www.ctsu.org) websites. * Patients must be able to take oral medications. * Patients must not have a \>= Grade 3 hypercholesterolaemia (defined by National Cancer Institute \[NCI\] Common Terminology Criteria for Adverse Events \[CTCAE\] version \[v\]5) within 28 days prior to sub-study registration. * Patients must not have EGFR sensitizing mutations, EGFR T790M mutation, ALK gene fusion, ROS 1 gene rearrangement, and BRAF V600E mutation unless they have progressed following all standard of care targeted therapy. * Patients must not have documented evidence of acute hepatitis or have an active or uncontrolled infection. * Patients with a known history of human immunodeficiency virus (HIV) seropositivity: * Must have undetectable viral load using standard HIV assays in clinical practice. * Must have CD4 count \>= 400/mcL. * Must not require prophylaxis for any opportunistic infections (i.e., fungal, mycobacterium avium complex \[mAC\], or pneumocystis pneumonia \[PCP\] prophylaxis). * Must not be newly diagnosed within 12 months prior to sub-study registration. * Patients must have progressed (in the opinion of the treating physician) following the 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 registration. CT and MRI scans must be submitted for central review via 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 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. * Absolute neutrophil count (ANC) \>= 1,500/mcl (obtained within 28 days prior to sub-study registration) * Platelet count \>= 100,000 mcl (obtained within 28 days prior to sub-study registration) * Hemoglobin \>= 9 g/dL (obtained within 28 days prior to sub-study registration) * Serum bilirubin =\< Institutional Upper Limit of Normal (IULN). For patients with liver metastases, bilirubin must be =\< 5 x IULN (within 28 days prior to sub-study registration) * Either alanine aminotransferase (ALT) or aspartate aminotransferase (AST) =\< 2 x IULN (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) (within 28 days prior to sub-study registration) * 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. * Patients must not be pregnant or nursing. Women/men of reproductive potential must have agreed to use an effective contraceptive method during the study and 6 months after study completion. 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 during the study and 6 months after study completion * 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate | From date of registration to a maximum of 3 years or death | Percentage of participants with a complete or partial, confirmed or unconfirmed response. 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Investigator-Assessed Progression-Free Survival (IA-PFS) | From date of registration to a maximum of 3 years or death | Time from date of 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: One or more of: 20% increase in sum of diameters of target lesions over smallest sum observed and absolute increase of at least 0.5cm; Unequivocal progression of non-measurable disease in opinion of the treating physician; Appearance of any new lesion/site; Death due to disease w/o prior progression or symptomatic deterioration Symptomatic deterioration: Global deterioration of health status requiring treatment discontinuation w/o objective evidence of progression |
| Overall Survival (OS) | From date of registration to a maximum of 3 years or death | Time from date of 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) | From date of registration to a maximum of 3 years or death | Time from date of first 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 response. 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 will be used as the date of progression. |
| Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | 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). |
Countries
United States
Participant flow
Pre-assignment details
64 participants were initially enrolled. Three participants were ineligible, one was not analyzable and one withdrew consent prior to starting the study drug. In all, 59 participants were eligible and included in the analysis: 25 in the squamous cohort and 34 in the non-squamous cohort.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1: Squamous Participants with squamous cell lung cancer | 25 |
| Cohort 2: Non-Squamous Participants with non-squamous cell lung cancer (adenocarcinoma, large cell, NSCLC NOS, mixed histology with any non-squamous component) | 34 |
| Total | 59 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 4 | 11 |
| Overall Study | Death | 4 | 0 |
| Overall Study | On Treatment | 2 | 1 |
| Overall Study | Other - not protocol specified | 1 | 3 |
| Overall Study | Progression/relapse | 14 | 18 |
| Overall Study | Refusal unrelated to adverse event | 0 | 1 |
Baseline characteristics
| Characteristic | Total | Cohort 1: Squamous | Cohort 2: Non-Squamous |
|---|---|---|---|
| Age, Continuous | 65.7 years | 63.9 years | 69.1 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 58 Participants | 25 Participants | 33 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants |
| Performance Status 0 | 15 Participants | 4 Participants | 11 Participants |
| Performance Status 1 | 44 Participants | 21 Participants | 23 Participants |
| Prior Lines of Treatment for Stage IV Disease 0 | 1 Participants | 1 Participants | 0 Participants |
| Prior Lines of Treatment for Stage IV Disease 1 | 25 Participants | 9 Participants | 16 Participants |
| Prior Lines of Treatment for Stage IV Disease 2 or more | 33 Participants | 15 Participants | 18 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 53 Participants | 23 Participants | 30 Participants |
| Sex: Female, Male Female | 26 Participants | 10 Participants | 16 Participants |
| Sex: Female, Male Male | 33 Participants | 15 Participants | 18 Participants |
| Smoking Status Current Smoker | 20 Participants | 10 Participants | 10 Participants |
| Smoking Status Former Smoker | 35 Participants | 15 Participants | 20 Participants |
| Smoking Status Never Smoker | 4 Participants | 0 Participants | 4 Participants |
| Study Biomarker Status BRCA1 Only | 4 Participants | 0 Participants | 4 Participants |
| Study Biomarker Status BRCA2 Only | 11 Participants | 5 Participants | 6 Participants |
| Study Biomarker Status LOH and BRCA1 | 4 Participants | 1 Participants | 3 Participants |
| Study Biomarker Status LOH and BRCA2 | 4 Participants | 3 Participants | 1 Participants |
| Study Biomarker Status LOH Only | 36 Participants | 16 Participants | 20 Participants |
| Weight Loss in the Past 6 Months 10 - < 20% | 6 Participants | 3 Participants | 3 Participants |
| Weight Loss in the Past 6 Months >= 20% | 1 Participants | 0 Participants | 1 Participants |
| Weight Loss in the Past 6 Months < 5% | 40 Participants | 16 Participants | 24 Participants |
| Weight Loss in the Past 6 Months 5 - < 10% | 11 Participants | 5 Participants | 6 Participants |
| Weight Loss in the Past 6 Months Unknown | 1 Participants | 1 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 50 / 59 |
| other Total, other adverse events | 57 / 59 |
| serious Total, serious adverse events | 32 / 59 |
Outcome results
Primary
Overall Response Rate
Percentage of participants with a complete or partial, confirmed or unconfirmed response. 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.
Time frame: From date of registration to a maximum of 3 years or death
Population: Eligible and evaluable participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1: Squamous | Overall Response Rate | 8 Percentage of participants |
| Cohort 2: Non-Squamous | Overall Response Rate | 12 Percentage of participants |
Secondary
Duration of Response (DoR)
Time from date of first 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 response. 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 will be used as the date of progression.
Time frame: From date of registration to a maximum of 3 years or death
Population: Eligible and evaluable participants who had a response
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1: Squamous | Duration of Response (DoR) | NA months |
| Cohort 2: Non-Squamous | Duration of Response (DoR) | 14.9 months |
Secondary
Investigator-Assessed Progression-Free Survival (IA-PFS)
Time from date of 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: One or more of: 20% increase in sum of diameters of target lesions over smallest sum observed and absolute increase of at least 0.5cm; Unequivocal progression of non-measurable disease in opinion of the treating physician; Appearance of any new lesion/site; Death due to disease w/o prior progression or symptomatic deterioration Symptomatic deterioration: Global deterioration of health status requiring treatment discontinuation w/o objective evidence of progression
Time frame: From date of registration to a maximum of 3 years or death
Population: Eligible and evaluable participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1: Squamous | Investigator-Assessed Progression-Free Survival (IA-PFS) | 2.9 months |
| Cohort 2: Non-Squamous | Investigator-Assessed Progression-Free Survival (IA-PFS) | 3.5 months |
Secondary
Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs
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).
Time frame: Duration of treatment and follow up until death or 3 years post registration
Population: Eligible participants who received at least one dose of protocol treatment
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1: Squamous | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Alkaline phosphatase increased | 1 Participants |
| Cohort 1: Squamous | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Anemia | 13 Participants |
| Cohort 1: Squamous | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Aspartate aminotransferase increased | 1 Participants |
| Cohort 1: Squamous | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Blood bilirubin increased | 1 Participants |
| Cohort 1: Squamous | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Chronic kidney disease | 1 Participants |
| Cohort 1: Squamous | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Confusion | 1 Participants |
| Cohort 1: Squamous | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Dyspnea | 2 Participants |
| Cohort 1: Squamous | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Fatigue | 5 Participants |
| Cohort 1: Squamous | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Generalized muscle weakness | 2 Participants |
| Cohort 1: Squamous | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Hypertension | 1 Participants |
| Cohort 1: Squamous | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Hypokalemia | 2 Participants |
| Cohort 1: Squamous | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Lymphocyte count decreased | 5 Participants |
| Cohort 1: Squamous | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Nausea | 1 Participants |
| Cohort 1: Squamous | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Alanine aminotransferase increased | 2 Participants |
| Cohort 1: Squamous | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Neutrophil count decreased | 2 Participants |
| Cohort 1: Squamous | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Personality change | 1 Participants |
| Cohort 1: Squamous | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Platelet count decreased | 3 Participants |
| Cohort 1: Squamous | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Rash maculo-papular | 1 Participants |
| Cohort 1: Squamous | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Vomiting | 1 Participants |
| Cohort 1: Squamous | Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | White blood cell decreased | 3 Participants |
Secondary
Overall Survival (OS)
Time from date of registration to date of death due to any cause. Participants last known to be alive are censored at date of last contact.
Time frame: From date of registration to a maximum of 3 years or death
Population: Eligible and evaluable participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1: Squamous | Overall Survival (OS) | 8.2 months |
| Cohort 2: Non-Squamous | Overall Survival (OS) | 7.8 months |