A Phase I/II Study of Nivolumab, Ipilimumab and Plinabulin in Patients With Recurrent Small Cell Lung Cancer

• ClinicalTrials.gov Identifier: NCT03575793
• Recruitment Status: Recruiting
• First Posted: July 3, 2018
• Last Update Posted: May 22, 2023
• Sponsor: Salma Sabbour
• Collaborators: BeyondSpring Pharmaceuticals Inc.; Bristol-Myers Squibb; Rutgers Cancer Institute of New Jersey
• Information provided by (Responsible Party): Salma Sabbour, Big Ten Cancer Research Consortium

Study Description

Brief Summary:

This is an open-label Phase I/II study, with a dose escalation part (Phase I) and a single-arm part (Phase II), in patients with recurrent SCLC who progressed after first-line platinum-based chemotherapy and who are candidates for second line therapy. No PK evaluation is planned in this study as nivolumab and ipilimumab are unlikely to alter plinabulin's PK, since the route of excretion is different.

Condition or disease	Intervention/treatment	Phase
Lung Cancer; SCLC	Drug: Nivolumab; Drug: Plinabulin; Drug: Ipilimumab	Phase 1; Phase 2

Detailed Description:

This is an open-label Phase I/II study, with a dose escalation part (Phase I) and a single arm part (Phase II), in patients with recurrent SCLC.

In the Phase I part, patients will receive plinabulin at escalating doses in combination with nivolumab and ipilimumab. Doses of study drug will be administered as intravenous (IV) infusions in 21 day cycles. Patients will receive all study drugs on Day 1 of each cycle. After 4 treatment cycles, ipilimumab is stopped and patients continue treatment with nivolumab and plinabulin every 2 weeks (maintenance period) or until disease progression, development of unacceptable toxicity or one of the protocol-defined reasons for treatment discontinuation occurs.

At least 3 patients will be enrolled in each cohort, starting at 20 mg/m2 of plinabulin. The dose of plinabulin will be escalated in sequential patient cohorts after the safety data from the first cycle is reviewed. Thereafter the dose of plinabulin will be escalated to 30 mg/m2, provided that dose-limiting toxicities (DLTs) are not observed per the specified criteria, until the RP2D is determined.

In the Phase II part, up to 26 patients will be treated with the triple combination of plinabulin (at RP2D) + nivolumab + ipilimumab. Patients will continue treatment until disease progression, development of unacceptable toxicity or one of the protocol-defined reasons for treatment discontinuation occurs.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 35 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I/II Study of Nivolumab, Ipilimumab and Plinabulin in Patients With Recurrent Small Cell Lung Cancer: Big Ten Cancer Research Consortium. BTCRC-LUN17-127
• Actual Study Start Date: September 6, 2018
• Estimated Primary Completion Date: September 2023
• Estimated Study Completion Date: September 2023

Arms and Interventions

Arm	Intervention/treatment
Experimental: Phase I (Dose Escalation): nivolumab, ipilimumab and plinabulin; On Day 1 in a 21-day cycle, all patients will receive nivolumab (1 mg/kg, IV), ipilimumab (3 mg/kg, IV) and plinabulin (escalating cohorts, IV). After 4 treatment cycles, ipilimumab will be discontinued and patients will continue treatment with nivolumab 240 mg and plinabulin every 2 weeks (maintenance period) until one of the end of treatment criteria occur. Plinabulin escalation is as follows: Level -1 : 13.5mg/m^2 Level 1 (start) : 20mg/m^2 Level 2 : 30mg/m^2	Drug: Nivolumab; A fully human immunoglobulin (Ig) G4 monoclonal antibody directed against the negative immunoregulatory human cell surface receptor programmed death-1 (PD-1,PCD-1,) with immune checkpoint inhibitory and antineoplastic activities.; Other Name: Opdivo; Drug: Plinabulin; Plinabulin (BPI-2358) is a synthetic, low molecular weight, new chemical entity originally developed by Nereus Pharmaceuticals, Inc., and now by BeyondSpring Pharmaceuticals, Inc. It belongs to the diketopiperazine class of compounds with a chemical name 2, 5-piperazinedione, 3-[[5-(1,1-dimethylethyl)-1H-imidazol-4-yl[methylene]-6-(phenylmethylene)-, (3Z,6Z) (trivial name t-butyl-dehydrophenylahistin).; Drug: Ipilimumab; Ipilimumab is a monoclonal antibody that works to activate the immune system by targeting CTLA-4, a protein receptor that downregulates the immune system.; Other Name: Yervoy
Experimental: Phase II: nivolumab, ipilimumab, and plinabulin; On Day 1 in a 21-day cycle, all patients will receive nivolumab (1 mg/kg, IV), ipilimumab (3 mg/kg, IV) and plinabulin (MTD from Phase I). After 4 treatment cycles, ipilimumab will be discontinued and patients will continue treatment with nivolumab 240 mg and plinabulin every 2 weeks (maintenance period) until one of the end of treatment criteria occur .	Drug: Nivolumab; A fully human immunoglobulin (Ig) G4 monoclonal antibody directed against the negative immunoregulatory human cell surface receptor programmed death-1 (PD-1,PCD-1,) with immune checkpoint inhibitory and antineoplastic activities.; Other Name: Opdivo; Drug: Plinabulin; Plinabulin (BPI-2358) is a synthetic, low molecular weight, new chemical entity originally developed by Nereus Pharmaceuticals, Inc., and now by BeyondSpring Pharmaceuticals, Inc. It belongs to the diketopiperazine class of compounds with a chemical name 2, 5-piperazinedione, 3-[[5-(1,1-dimethylethyl)-1H-imidazol-4-yl[methylene]-6-(phenylmethylene)-, (3Z,6Z) (trivial name t-butyl-dehydrophenylahistin).; Drug: Ipilimumab; Ipilimumab is a monoclonal antibody that works to activate the immune system by targeting CTLA-4, a protein receptor that downregulates the immune system.; Other Name: Yervoy

Outcome Measures

Primary Outcome Measures :

1. Phase I: Maximum Tolerated Dose (MTD) [ Time Frame: 9 Months ]
   Establish MTD of plinabulin in combination with nivolumab and ipilimumab for patients with recurrent SCLC
2. Phase II: Progression-Free Survival (PFS) [ Time Frame: 36 Months ]
   Determine if the addition of plinabulin (at the 30 mg/m2 dose) to double checkpoint inhibition (PD-1 and CTLA-4) for recurrent SCLC will improve PFS (the time from treatment assignment to the date of the first documented tumor progression, or death due to any cause, whichever occurred first).

Secondary Outcome Measures :

1. Assess Adverse Events [ Time Frame: 36 Months ]
   Assess toxicity and tolerability of the combination of nivolumab, ipilimumab and plinabulin using CTCAE v5
2. Assess immune-related adverse events (irAEs) [ Time Frame: 36 Months ]
   Measure the frequency of immune-related adverse events (irAEs). irAE's are defined as any treatment-related AE that is inflammatory in nature, consistent with the mechanism of action of immunotherapy and generally medically manageable with topical and/or systemic immunosuppressants.
3. Proportion of subjects with a confirmed objective response [ Time Frame: 36 Months ]
   Determine the proportion of patients with a confirmed objective response in the 2 arms of the Phase II part (defined as the number of patients with a best overall response of complete response [CR] or PR divided by the number of assigned patients).
4. Clinical Benefit Rate [ Time Frame: 36 Months ]
   Estimate clinical benefit rate (CBR: complete response, partial response, or stable disease).
5. 6-Month Progression-Free Survival [ Time Frame: 6 Months ]
   Estimate 6-month (±4 weeks) PFS.
6. 1-year Overall Survival [ Time Frame: 12 Months ]
   Estimate 1-year Overall Survival
7. Overall Survival [ Time Frame: 36 Months ]
   Estimate Overall Survival

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

The patients must satisfy all of the following inclusion/exclusion criteria in order to be eligible for the study:

• Must have signed and dated written informed consent form in accordance with regulatory and institutional guidelines.
• Males and females aged >18 years at time of consent.
• Histological or cytological confirmed extensive-stage SCLC
• Patients who progressed after at least 1 platinum-based chemotherapy regimen. Patients with platinum resistance (defined as recurrence or progression of disease within 90 days of completion of the platinum-based regimen) are eligible. For phase II, patients also must have been treated with at least one prior line of PD-1/PD-L1 therapy.
• Measurable disease according to RECIST v1.1 (Section 8) obtained by imaging within 28 days prior to study registration.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 within 14 days before registration and minimum life expectancy of at least 12 weeks.
• Treatment to be initiated at least 2 weeks since last dose of prior systemic anticancer therapy (chemotherapy, radiation, and/or surgery.
• Recovery to grade 1 of any clinically significant toxicity (excluding alopecia, grade 2 fatigue, vitiligo, endocrinopathies on stable replacement therapy) prior to initiation of study drugs.

• Female patients of childbearing potential have a negative pregnancy test at baseline. Females of childbearing potential are defined as sexually mature women without prior hysterectomy or who have had any evidence of menses in the past 12 months. However, women who have been amenorrheic for 12 or more months are still considered to be of childbearing potential if the amenorrhea is possibly due to prior chemotherapy, anti estrogens, or ovarian suppression.

  • Women of childbearing potential (i.e., menstruating women) must have a negative urine pregnancy test (positive urine tests are to be confirmed by serum test) documented within 14 days of study registration and within the 24-hour period prior to the first dose of study drug.
  • Sexually active women of childbearing potential enrolled in the study must agree to use 2 forms of accepted methods of contraception during the course of the study and for 23 weeks after their last dose of study drug. Effective birth control includes (a) intrauterine device plus 1 barrier method; (b) on stable doses of hormonal contraception for at least 3 months (e.g., oral, injectable, implant, transdermal) plus one barrier method; (c) 2 barrier methods. Effective barrier methods are male or female condoms, diaphragms, and spermicides (creams or gels that contain a chemical to kill sperm); or (d) a vasectomized partner.
  • For male patients who are sexually active and who are partners of premenopausal women: agreement to use 2 forms of contraception as in criterion 9b above during the treatment period and for 31 weeks after the last dose of study drug.

• Adequate laboratory values.

  • Absolute neutrophil count ≥1,000/µL
  • Platelet count ≥100,000/µL
  • Hemoglobin ≥9.0 g/dL
  • Total bilirubin ≤1.5 x upper limit of normal (ULN) or ≤3 x ULN for subjects with Gilbert's disease
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3.0 x ULN (≤5 x ULN if evidence of hepatic involvement by malignant disease)
  • Creatinine ≤ 1.5 x ULN or estimated glomerular filtration rate (eGFR) ≥40 mL/min/1.73m2
  • Lipase and Amylase ≤1.5 x ULN. Subjects with Lipase >1.5 x ULN may enroll if there are neither clinical nor radiographic signs of a pancreatitis.

Exclusion Criteria

Patients with any of the following will be excluded from participation in the study.

• Active interstitial lung disease (ILD) or pneumonitis or a history of ILD or pneumonitis requiring treatment with steroids. Prior history of radiation pneumonitis is allowed if pneumonitis was restricted to the field of radiation.
• History of ileus or other significant gastrointestinal disorder known to increase the risk of ileus or chronic bowel hypomotility
• 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 23 weeks (female) or 31 weeks (male) after the last dose of study drug.
• Must not have received CTLA-4 targeted therapy previously
• Treatment with any investigational agent within 28 days prior to registration for protocol therapy. Vaccination for SARS-CoV-2 is allowed as well as any therapy as required for the treatment of active COVID 19 infection.
• Known active symptomatic central nervous system (CNS) metastases and/or carcinomatous meningitis. Patients with neurological symptoms must undergo a head computed tomography (CT) scan or brain magnetic resonance imaging (MRI) to exclude brain metastasis. Patients whose brain metastases have been treated may participate provided there is no evidence of progression for at least 2 weeks after CNS-directed treatment, as ascertained by clinical examination or brain imaging.
• Known history of human immunodeficiency virus (HIV) or active hepatitis B (by surface antigen expression or polymerase chain reaction [PCR]) or active hepatitis C (by PCR) infection. NOTE: HIV testing is not required; Hepatitis B and C testing are required at screening.
• Diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to study registration.
• Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e., with use of disease modifying agents, corticosteroids, or immunosuppressive drugs) or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents. Vitiligo, alopecia, hypothyroidism only requiring hormone replacement, psoriasis not requiring systemic treatment, celiac disease controlled by diet alone or conditions not expected to recur in the absence of an external trigger are permitted.
• A condition requiring systemic treatment with corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days prior to administration of study drugs.
• History of psychiatric illness or social situations that would limit compliance with study requirements. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the patient's participation for the full duration of the trial, or is not in the best interest of the patient to participate, in the opinion of the treating investigator.
• Prior malignancies (except non-melanoma skin cancers, and the following in situ cancers: bladder, gastric, colon, endometrial, cervical/dysplasia, melanoma, or breast) unless a complete remission was achieved at least 2 years prior to study entry.
• Documented history of a cerebral vascular event (stroke or transient ischemic attack), unstable angina, myocardial infarction, or cardiac symptoms consistent with New York Heart Association (NYHA) Class III-IV within 6 months prior to their first dose of study drugs.
• Evidence of ongoing inadequately controlled hypertension (defined as baseline systolic blood pressure >160 mmHg or diastolic blood pressure >100 mmHg).
• Any active grade 3 or higher viral, bacterial, or fungal infection within 2 weeks of the first dose of the study drugs. Routine antimicrobial prophylaxis is permitted.

Contacts and Locations

Contacts

Contact: Salma Jabbour, MD; 732-253-3939; jabbousk@cinj.rutgers.edu

Contact: Ahran Lee; 317-634-5842 ext 14; alee@hoosiercancer.org

Locations

United States, California

City of Hope; Recruiting

Duarte, California, United States, 91010

Contact: Suzanne Funmaker sfunmaker@coh.org

Principal Investigator: Jyoti Malhotra, MD

United States, Florida

Moffitt Cancer Center; Recruiting

Tampa, Florida, United States, 33612

Contact: Meghan Christie 813-745-4625 Meghan.Christie@moffitt.org

Principal Investigator: Alberto Chiappori, MD

United States, Illinois

University of Illinois Cancer Center; Recruiting

Chicago, Illinois, United States, 60612

Contact: Lauren Talasnik 312-996-6275 talasnik@uic.edu

Principal Investigator: Lawrence Feldman, MD

United States, Indiana

Indiana University Melvin and Bren Simon Cancer Center; Recruiting

Indianapolis, Indiana, United States, 46202

Contact: Vanessa Williams 317-274-0292 vanewill@iu.edu

Principal Investigator: Nassser Hanna, MD

United States, Michigan

Henry Ford Health System; Terminated

Detroit, Michigan, United States, 48202

United States, Minnesota

University of Minnesota; Recruiting

Minneapolis, Minnesota, United States, 55455

Contact: Sarah Smith 612-624-6968 pett0127@umn.edu

Principal Investigator: Naomi Fujioka, MD

United States, New Jersey

Rutgers Cancer Institute of New Jersey; Recruiting

New Brunswick, New Jersey, United States, 08903

Contact: Jyoti Malhotra 732-235-7521 Jm1940@cinj.rutgers.edu

Contact: Michelle Orlick 732-235-6048 orlickmi@cinj.rutgers.edu

Principal Investigator: Jyoti Malhotra, MD

United States, Tennessee

Erlanger Health System; Terminated

Chattanooga, Tennessee, United States, 37403

Sponsors and Collaborators

Salma Sabbour

BeyondSpring Pharmaceuticals Inc.

Bristol-Myers Squibb

Rutgers Cancer Institute of New Jersey

Investigators

• Principal Investigator: Salma Jabbour, MD; Rutgers Cancer Institute of New Jersey

More Information

• Responsible Party: Salma Sabbour, Sponsor Investigator, Big Ten Cancer Research Consortium
• ClinicalTrials.gov Identifier: NCT03575793
• Other Study ID Numbers: BTCRC-LUN17-127
• First Posted: July 3, 2018
• Last Update Posted: May 22, 2023
• Last Verified: January 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Nivolumab; Lung Neoplasms; Small Cell Lung Carcinoma; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases; Carcinoma, Bronchogenic; Bronchial Neoplasms; Ipilimumab; Antineoplastic Agents, Immunological; Antineoplastic Agents; Immune Checkpoint Inhibitors; Molecular Mechanisms of Pharmacological Action