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

This is an open-label Phase I/II study, with a dose escalation part (Phase I) and a 2-arm
randomized 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, approximately 40 patients will be randomized in a 1:1 ratio to receive
either nivolumab + ipilimumab (Arm NI) or the triple combination of plinabulin (at RP2D) +
nivolumab + ipilimumab (Arm PNI). Patients will continue treatment until disease progression,
development of unacceptable toxicity or one of the protocol-defined reasons for treatment
discontinuation occurs.

Inclusion Criteria:

- 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 with availability of
representative baseline tumor tissue (10 slides; archived or on-study biopsy). If
patient already has FoundationOne testing results, baseline tumor tissue is not
required to meet eligibility.

- 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.

- 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) 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.

- 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:

- Active interstitial lung disease (ILD) or pneumonitis or a history of ILD or
pneumonitis requiring treatment with steroids

- 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 PD-1, PD-L1 or CTLA-4 targeted therapy previously

- Treatment with any investigational agent within 28 days prior to registration for
protocol therapy.

- Known active 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 they show radiographic
stability (defined as 2 brain images obtained after treatment to the brain metastases
at least 4 weeks apart and show no evidence of intracranial progression)

- 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.

- 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.