Lurbinectedin, Nivolumab, and Ipilimumab for the Treatment of Patients with Relapsed or Refractory Small Cell Lung Cancer

Inclusion Criteria

• Histologic or cytologic diagnosis of small cell lung cancer (SCLC). For patients enrolling in the Phase I, dose escalation component, histologic or cytologic diagnosis of ANY high grade neuroendocrine carcinoma, including large cell neuroendocrine carcinoma (LCNEC) is also allowed
• Recurrence to at least one prior treatment with a platinum containing regimen (cisplatin or carboplatin) including limited stage (LS) and extensive stage (ES) initial presentations * NOTE: In patients with SCLC, the most frequent platinum-doublet used is etoposide-carboplatin. However, etoposide-cisplatin and irinotecan, or topotecan combined with either carboplatin or cisplatin, can sometimes be used and would be allowed for the purposes of trial enrollment and eligibility.
• Prior immune checkpoint inhibitors (monotherapy or combinations) are allowed
• Willing/able to provide written informed consent/assent for the trial
• Have measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1
• Have a performance status of 0 - 1 on the Eastern Cooperative Oncology Group (ECOG) performance scale
• Absolute neutrophil count (ANC) >= 1,500/mcL (performed within 28 days of enrollment)
• Platelets >= 100,000/mcL (performed within 28 days of enrollment)
• Hemoglobin >= 9 g/dL (blood transfusions are permitted to meet inclusion criteria) (performed within 28 days of enrollment)
• Serum creatinine =< 1.5 x upper limit of normal (ULN) OR calculated creatinine clearance >= 50 mL/min (using the Cockcroft Gault formula) (performed within 28 days of enrollment)
• Serum total bilirubin =< 1.5 x ULN OR direct bilirubin =< 1 x ULN for subjects with total bilirubin levels > 1.5 ULN (performed within 28 days of enrollment)
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x ULN (performed within 28 days of enrollment)
• International normalized ratio (INR) or prothrombin time (PT) and activated partial thromboplastin time (aPTT) =< 2.0 x ULN unless subject is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range (performed within 28 days of enrollment)
• Albumin >= 3.0 g/dL (performed within 28 days of enrollment)
• Women of childbearing potential (WOCBP) must have a negative urine or serum pregnancy test within 72 hours from receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
• WOCBP should agree to use 2 methods of birth control or abstain from heterosexual activity for the course of the study through 5 months after the last dose of study medication or should be surgically sterile * NOTE: A woman is considered to be of “reproductive potential” (WOCBP) 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, she is responsible for beginning contraceptive measures
• Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 7 months after the last dose of study therapy * NOTE: In addition to routine contraceptive methods, “effective contraception” also includes heterosexual celibacy and surgery intended to prevent pregnancy (vasectomy). However, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures, he is responsible for beginning contraceptive measures
• Members of all races and ethnic groups are eligible for this trial

Exclusion Criteria

• Excluded are patients who upon relapse may be still considered for a salvage concurrent chemo-radiation approach
• Is currently participating in a study of an investigational agent or device and received or used the investigational agent or device within 4 weeks of the first dose of treatment
• Has a diagnosis of immunodeficiency or is receiving systemic steroid or any other form of immunosuppressive therapy within 7 days prior to the first dose of treatment * NOTE: Systemic steroid doses of =< 10 mg of prednisone daily or its equivalent are allowed in patients receiving physiologic replacement steroid doses
• Has a known history of active TB (Bacillus tuberculosis)
• Hypersensitivity to lurbinectedin, ipilimumab and/or nivolumab or any of its excipients
• Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier
• Has had targeted small molecule therapy, or standard fractionated radiotherapy within 2 weeks, chemotherapy within 3 weeks and stereotactic radiotherapy within 1 week prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to a previously administered agent * NOTE: ** Subjects with =< grade 2 neuropathy are an exception to this criterion and may qualify for the study ** If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy
• Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer. Other malignancies that remain without evidence of disease or recurrence, 2 years or more after curative therapy are also considered part of this exception
• 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 2 weeks prior to the first dose of trial treatment 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 to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability
• Has any of the following concomitant diseases/conditions: * History or presence of unstable angina, myocardial infarction, congestive heart failure, or clinically significant valvular heart disease within last year * Symptomatic arrhythmia or any uncontrolled arrhythmia requiring ongoing treatment * History of idiopathic, pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT)-scan. History of radiation pneumonitis in radiation field (fibrosis) is permitted, as long as it is asymptomatic, and no steroids are needed * Myopathy or any clinical situation that causes significant and persistent elevation of creatine phosphokinase (CPK) (> 2.5 x ULN in two different determinations performed one week apart)
• Any diagnosis of autoimmune disease (confirmed by medical records or appropriate laboratory testing) is not allowed
• Has an active infection requiring systemic therapy
• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject’s participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator
• 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 the pre-screening or screening visit through 120 days after the last dose of trial treatment
• Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies), active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected)
• Has received a live vaccine within 30 days of start of study therapy * 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
• Patients who had a prior grade >= 3 immune-related adverse event (AE) (e.g. pneumonitis, hepatitis, colitis, endocrinopathy) with prior immunotherapy (e.g. cancer vaccine, cytokine, etc.)
• Patients must not be pregnant or nursing due to risk of fetal or nursing infant harm. WOCBP must have agreed to use an effective contraceptive method
• Subjects with interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity
• Prisoners or subjects who are involuntarily incarcerated
• Subjects who are compulsorily detained for treatment of either a psychiatric or physical (e.g., infectious disease) illness