Rucaparib and Pembrolizumab Maintenance Therapy in Treating Patients with Stage IV Non-squamous Non-small Cell Lung Cancer

Status: Active

Description

This phase I / II trial studies how well rucaparib and pembrolizumab works as maintenance therapy (therapy meant to help primary therapy succeed and to help keep cancer from coming back) in treating patients with stage IV non-squamous non-small cell lung cancer. Rucaparib blocks an enzyme in cells called PARP; in tumor cells, this leads to increased cell death. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body’s immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving rucaparib and pembrolizumab as maintenance therapy may work better in treating patients with non-squamous non-small cell lung cancer compared to maintenance therapy with pembrolizumab and a chemotherapy drug called pemetrexed.

Eligibility Criteria

Inclusion Criteria

  • Be willing and able to provide written informed consent/assent for the trial
  • Have a life expectancy of at least 3 months
  • Have a histologically confirmed diagnosis of stage IV non-squamous NSCLC whose tumors do not have an epidermal sensitizing growth factor (EGFR) mutation or BRAF mutation or rearrangements in ALK (anaplastic lymphoma kinase) or ROS-1 and have at least one measurable lesion based on RECIST v1.1
  • Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) performance scale
  • Absolute neutrophil count (ANC) >= 1,500 /mcL (within 14 days of enrollment)
  • Platelets >= 100,000 / mcL (within 14 days of enrollment)
  • Hemoglobin >= 9 g/dL without transfusion (within 14 days of enrollment) or erythropoietin (EPO) dependency (within 7 days of assessment)
  • Serum creatinine =< 1.5 X upper limit of normal (ULN) OR measured or calculated creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) >= 60 mL/min for subject with creatinine levels > 1.5 X institutional ULN (within 14 days of enrollment) * Creatinine clearance should be calculated per institutional standard
  • Serum total bilirubin =< 1.5 X ULN OR direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 ULN (within 14 days of enrollment)
  • Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X ULN OR =< 5 X ULN for subjects with liver metastases (within 14 days of enrollment)
  • Albumin >= 2.5 g/dL (within 14 days of enrollment)
  • International normalized ratio (INR) or prothrombin time (PT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants (within 14 days of enrollment)
  • Activated partial thromboplastin time (aPTT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants (within 14 days of enrollment)
  • Female subject of childbearing potential should have a serum pregnancy within 14 days of enrollment and 72 hours prior to receiving the first dose of study medications
  • Female subjects of childbearing potential must be willing to use a highly effective method of contraception for the course of the study through 180 days after the last dose of study medications * Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject
  • Male subjects of childbearing potential must agree to use an adequate method of contraception, starting with the first dose of study therapy through 180 days after the last dose of study therapy * Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject
  • Adequate tissue sample for correlative studies. A new sample is not necessary if archival specimen is available and has adequate amount of tumor content (at least 30%). This needs to be determined by a pathologist at the individual institution. If no archival tissue sample is available and/or the archival sample do not meet the requirement of 30% tumor content, then a screening tissue biopsy should take place

Exclusion Criteria

  • Received previous systemic therapy for stage IV NSCLC
  • Received radiation to the lungs > 30 Gy =< 6 months of enrollment
  • Received palliative radiation within 7 days of enrollment
  • Had prior treatment with any other anti-PD-1, PD-L1, or PD-L2 agent or an antibody targeting other immune-regulatory receptors or mechanisms
  • Received prior treatment with a PARP inhibitor
  • Has a known history of prior malignancy except if the patient has undergone potentially curative therapy with no evidence of that disease recurrence for 5 years since initiation of that therapy. Note: the time requirement for no evidence of disease for 5 years does not apply to the NSCLC tumor for which a subject is enrolled in the study. The time requirement also does not apply to subjects who underwent successful definitive resection of basal cell carcinoma of the skin, superficial bladder cancer, squamous cell carcinoma of the skin, in situ cervical cancer, or other in situ cancers
  • Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to enrollment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior enrollment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability
  • Has active autoimmune disease that has required systemic treatment within the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs) * Note: Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
  • Subjects requiring daily corticosteroids > 10 mg of prednisone (or its equivalent) would be excluded from the study * Note: Subjects with asthma that require intermittent use of bronchodilators, inhaled steroids, or local steroid injections would NOT be excluded from the study
  • Has evidence of interstitial lung disease or a history of non-infectious pneumonitis that required oral or intravenous glucocorticoids to assist with management * Note: Lymphangitic spread of the NSCLC is not exclusionary
  • Has an active infection requiring systemic therapy
  • Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
  • Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with informed consent through 180 days after the last dose of trial treatment
  • Has a diagnosis of immunodeficiency (including human immunodeficiency virus [HIV] or acquired immunodeficiency syndrome [AIDS]-related illness) or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to enrollment
  • Has a known history of active TB (Bacillus tuberculosis)
  • Has known active hepatitis B or hepatitis C
  • Has received a live vaccine within 30 days of enrollment * Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist) are live attenuated vaccines, and are not allowed
  • A medical condition that requires daily systemic corticosteroids, greater than the equivalent of 10 mg of prednisone * Note: Corticosteroids administered as part of pre-medications or supportive medications (as in the case of dexamethasone as an anti-emetic administered with pemetrexed) are allowed

Locations & Contacts

Michigan

Ann Arbor
University of Michigan Comprehensive Cancer Center
Status: Active
Contact: Nithya Ramnath
Phone: 734-232-6789
Email: nithyar@med.umich.edu

Missouri

Saint Louis
Siteman Cancer Center at Washington University
Status: Active
Contact: Daniel Morgensztern
Phone: 314-747-7409

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. To determine the progression free survival (PFS) of the combination of rucaparib camsylate (rucaparib) and pembrolizumab maintenance therapy in patients with stage IV non-squamous non-small cell lung cancer (NSCLC) with complete response (CR), partial response (PR), or stable disease (SD) after completing induction therapy with four cycles of carboplatin, pemetrexed and pembrolizumab (CPP).

SECONDARY OBJECTIVES:

I. To evaluate the safety and tolerability profile of pembrolizumab and rucaparib.

II. To evaluate the overall survival (OS) in patients treated with maintenance pembrolizumab and rucaparib following induction therapy with CPP.

III. Evaluate response based on immune related Response Evaluation Criteria in Solid Tumors (RECIST) (irRECIST) as proposed by Wolchok et. al. and compare with response as calculated by RECIST version (v)1.1.

EXPLORATORY OBJECTIVES:

I. To evaluate genomic correlates of response to combination maintenance therapy with rucaparib and pembrolizumab.

II. To evaluate the correlation between germline and somatic mutations in genes in the homologous repair pathway and association with improved PFS to the combination of rucaparib and pembrolizumab.

OUTLINE:

INDUCTION PHASE: Patients receive pembrolizumab intravenously (IV) over 30 minutes, pemetrexed IV over 10 minutes, and carboplatin IV over 15-60 minutes on day 1. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity.

MAINTENANCE PHASE: Patients who achieve CR, PR, or SD receive pembrolizumab IV over 30 minutes on day 1 and rucaparib camsylate orally (PO) twice daily (BID) on days 1-21. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days. Severe adverse events that occur within 90 days of the end of treatment or before initiation of a new anti-cancer treatment will be followed and recorded. Patients who discontinue study treatment without disease progression are followed every 12 weeks. Follow up continues after disease progression for all patients every 6 months for up to 5 years.

Trial Phase & Type

Trial Phase

Phase I/II

Trial Type

Treatment

Lead Organization

Lead Organization
University of Michigan Comprehensive Cancer Center

Principal Investigator
Nithya Ramnath

Trial IDs

Primary ID UMCC 2018.033
Secondary IDs NCI-2019-01067
Clinicaltrials.gov ID NCT03559049