Rucaparib and Nivolumab in Treating Patients with Stage IV Extensive Stage Small Cell Lung Cancer
- Patients with histologically or cytologically confirmed stage IV, extensive stage, small cell lung cancer who achieved either PR or CR per RECIST 1.1 post frontline chemotherapy with platinum doublet (cisplatin/carboplatin-etoposide or carboplatin/cisplatin-irinotecan). * No later than 6W after the last dose of platinum-based chemotherapy in cycle 4 (or later cycles). * Subjects may have measurable (PR status) or non-measurable (CR) disease.
- Eastern Cooperative Oncology Group (ECOG) performance status =< 2.
- Absolute neutrophil count (ANC) >= 1.5 x 10^9/L.
- Platelets >= 100 x 10^9/L.
- Hemoglobin >= 9 g/dL.
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3 x upper limit of normal (ULN); if liver metastases, then =< 5 x ULN.
- Bilirubin =< 1.5 x ULN; < 2 x ULN if hyperbilirubinemia is due to Gilbert’s syndrome.
- Measured or calculated creatinine clearance (CrCL) >= 30 mL/min. For calculated CrCL, the Cockcroft Gault formula or institutional standard formula can be used.
- Written informed consent: Signed and dated informed consent of the subject must be available before start of any specific trial procedures. The subject must be able to understand the nature, importance and individual consequences of the clinical trial.
- Prior therapy with any antibody/drug targeting T-cell co-regulatory proteins (immune checkpoints).
- Also excluded is major surgery within 4 weeks of initiation of study medication.
- Current use of immunosuppressants is prohibited EXCEPT for the following: * Intranasal, inhaled, topical steroids, or local steroid injection (e.g., intra-articular injection); * Systemic corticosteroids at physiologic doses =< 10 mg/day of prednisone or equivalent; * Steroids as premedication for hypersensitivity reactions (e.g., computed tomography [CT] scan premedication).
- Prior organ transplantation, including allogeneic stem cell transplantation.
- Active infection requiring systemic therapy.
- Human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS): Known history of testing positive for human immunodeficiency virus or known acquired immunodeficiency syndrome.
- Autoimmune disease: Active autoimmune disease including autoimmune paraneoplastic syndromes that might deteriorate when receiving an immunostimulatory agent. * Patients with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible.
- Persisting toxicity related to prior therapy (National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events (CTCAE) version [v.] 5 grade > 1); however, alopecia, sensory neuropathy grade =< 2, or other grade =< 2 not constituting a safety risk based on investigator's judgment are acceptable.
- Pregnancy and contraception: Pregnancy is an exclusionary criterion.
- Female patients or partners of male patients are considered to be of childbearing potential unless one of the following applies: * Considered permanently sterile. Permanent sterilization includes hysterectomy, bilateral salpingectomy, and/or bilateral oophorectomy * Postmenopausal, defined as no menses for at least 12 months without an alternative medical cause. A high follicle-stimulating hormone (FSH) level consistently in the postmenopausal range (30 mIU/mL or higher) may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy; however, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient to confirm a postmenopausal state.
- To be eligible for enrollment, female patients of childbearing potential must have a negative serum or urine pregnancy test result within two weeks prior to administration of study treatment. Once on-study, pregnancy status of female patients will be evaluated per standard of care.
- Women of childbearing potential must not consider getting pregnant, and must avoid pregnancy during the study and for at least 6 months after the last dose of rucaparib or nivolumab, or longer if requested by local authorities.
- Male patients of reproductive potential with female partners of childbearing potential must not consider getting pregnant, and must avoid pregnancy during the study and for at least 6 months after the last dose of rucaparib or nivolumab, or longer if requested by local authorities.
- Male patients are required to use a condom during sex with a partner to avoid the possibility of exposing the partner to rucaparib or nivolumab, regardless of whether the partner is a woman of childbearing potential or not. Male patients must not make semen donations during treatment and for 6 months following the last dose of rucaparib or nivolumab. Males who are sexually active with women of childbearing potential must agree to follow instructions for method(s) of contraception for the duration of treatment and 6 months after last dose of nivolumab or rucaparib.
- Female and male patients of reproductive potential must practice highly effective methods (failure rate < 1% per year) of contraception with their partners during treatment, and for 6 months following the last dose of rucaparib or nivolumab, or longer if requested by local authorities. Highly effective contraception includes: * Ongoing use of progesterone-only injectable or implantable contraceptives; * Placement of an intrauterine device (IUD) or intrauterine system (IUS); * Bilateral tubal occlusion; * Sexual abstinence as defined as complete or true abstinence, acceptable only when it is the usual and preferred lifestyle of the patient; periodic abstinence (e.g., calendar, post-ovulation methods) is not acceptable; * Male sterilization, with appropriate post-vasectomy documentation of absence of sperm in ejaculate.
- Patients should be instructed to notify the investigator if pregnancy is discovered either during or within 6 months of completing treatment with rucaparib or nivolumab.
- Other severe acute or chronic medical conditions (including immune colitis, inflammatory bowel disease, immune pneumonitis, pulmonary fibrosis or psychiatric conditions including recent [within the past year] or active suicidal ideation or behavior) or laboratory abnormalities that may increase the risk associated with study participation, study treatment administration and/or may interfere with the interpretation of study results and/or in the judgment of the investigator, would make the patient inappropriate for entry into this study.
- Vaccination: Vaccination within 4 weeks of the first dose of nivolumab and while on trial is prohibited EXCEPT for administration of inactivated vaccines.
- Hypersensitivity: Known prior severe hypersensitivity to nivolumab or rucaparib or any components in their formulations, including known severe hypersensitivity reactions to monoclonal antibodies and PARP inhibitors (NCI CTCAE v5 grade >= 3).
- Cardiovascular disease: Clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months prior to enrollment), unstable angina, congestive heart failure ( >= New York Heart Association Classification class II), or serious cardiac arrhythmia requiring medication.
- Participation in other clinical trials involving an investigational drug during the present clinical trial or within the last 30 days, or five terminal phase half-lives of the drug whichever is longer, prior to baseline assessment (this also includes investigational formulation of market products).
- Subjects who received platinum in the adjuvant or neoadjuvant setting are eligible; however, subjects may not have relapsed within 6 months of the last dose of prior platinum therapy.
- Untreated central nervous system (CNS) metastases or leptomeningeal carcinomatosis.
- Patients with a prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the safety or efficacy assessment of this trial’s investigational regimen should be excluded.
- Patients with active pneumonitis will be excluded from the study.
- Current use of warfarin, Coumadin, Tizanidine and/or aripiprazole is excluded. Use of other agents/medications that affect CYP will be reviewed for eligibility at the discretion of the treating physician.
- Subjects with active autoimmune disease and subjects requiring systemic corticosteroids (> 10 mg daily prednisone equivalent) within 14 days of study registration. Subjects taking systemic corticosteroids for percutaneous coronary intervention (PCI) treatment are eligible.
I. To evaluate progression free survival of the combination rucaparib and nivolumab as maintenance therapy in platinum sensitive (as defined by complete response [CR]/partial response [PR] via Response Evaluation Criteria in Solid Tumors [RECIST] version [V]1.1) extensive stage small cell lung cancer (SCLC) after response to initial platinum-based therapy.
I. To evaluate the disease control rate after 8 weeks, 16 weeks and 24 weeks of treatment.
II. To evaluate 1-year and 2-year overall survival.
III. To evaluate potential biomarkers for durability of response, especially tumor mutation burden.
IV. To assess the toxicity profile of experimental drug combination.
V. To evaluate objective response rate at 8 weeks, 16 weeks and 24 weeks.
VI. To evaluate quality of life.
VII. To explore in a preliminary manner the response of genomic subsets to treatment focusing on tumor mutation burden, cMEK and TP53 mutation analysis of tumor tissue and evaluation of response, using the Oncology Research Information Exchange Network (ORIEN) consortium whole exome sequencing platform to evaluate tumor mutation burden, somatic and germline mutations.
EXPLORATORY CORRELATIVE OBJECTIVES:
I. To evaluate, in a preliminary manner, immune-related response markers as follows:
Ia. Percentage of CD4 T cells and CD8 T cells expressing PD-1 and Ki-67.
Ib. Percentage of polyfunctional effector CD4 T cells and CD8 T cells (CD101+ and CD38+) producing IFN gamma and TNF alpha.
Ic. Percentage of effector CD4 T cells and CD8 T cells expressing CD38, HLA-DR, CD28, ICOS, CD27, and low Bcl2 levels.
II. To correlate, when available, tumor mutation burden and specific gene mutations with treatment using results of sequencing of tissue collected and germline mutation testing from the Markey Cancer Center Total Cancer Care (ORIEN) protocol.
Patients receive rucaparib orally (PO) twice daily (BID) on days 1-28 and nivolumab intravenously (IV) on day 1. Cycles repeat every 28 days for 24 months in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 6 months for up to 3 years.
Trial Phase Phase II
Trial Type Treatment
University of Kentucky / Markey Cancer Center
- Primary ID MCC-18-LUN-107-CLO-PMC
- Secondary IDs NCI-2019-03335
- Clinicaltrials.gov ID NCT03958045