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Title An Open-Label, Single Arm Phase II Study of Nivolumab in Combination with Ipilimumab as first line-therapy in stage IV Non-Small Cell Lung Cancer (NSCLC)

IRB BRMY1516

CC 16-060

Hospital Florida Weston

Stage Stage 4

Phase Phase 2

Disease Lung - NSCLC (Non-small cell lung cancer)

Drug Ipilimumab, Nivolumab

Description

Primary Objectives

• To determine the objective response rate (ORR) as assessed by Blinded Independent Central Review per RECIST 1.1 in PD-L1+ (membranous staining in ≥ 1% tumor cells) Stage IV NSCLC subjects treated with nivolumab in combination with ipilimumab as first line therapy.

Secondary Objectives

• To assess progression free survival (PFS), PFS rate at 6 months and duration of response (DOR) in PD L1+ treated subjects, based on blinded independent central review assessment.

Exploratory Objectives

• To assess safety and tolerability, pharmacokinetics and immunogenicity, and explore exposure-safety and exposure-efficacy relationships of nivolumab in combination with ipilimumab as first line therapy.
• To assess ORR, PFS, PFS rate at 6 months and DOR in PD L1- (membranous staining in < 1% tumor cells) treated subjects.
• To assess OS in PD-L1+ and PD-L1- treated subjects.

Inclusion Criteria

1. Signed Written Informed Consent
   • Subjects must have signed and dated an IRB/IEC approved written informed consent form in accordance with regulatory and institutional guidelines. This must be obtained before the performance of any protocol related procedures that are not part of normal subject care.
   • Subjects must be willing and able to comply with scheduled visits, treatment schedule, and laboratory testing.
2. Target Population
   • ECOG Performance Status of 0-1
   • Subjects with histologically confirmed stage IV NSCLC per the 7th International Association for the Study of Lung Cancer classification (IASLC)43 of squamous or nonsquamous histology, with no prior systemic anticancer therapy (including EGFR and ALK inhibitors) given as primary therapy for advanced or metastatic disease. Prior definitive chemoradiation for locally advanced disease is permitted as long as the last administration of chemotherapy or radiotherapy (which ever was given last) occurred at least 6 months prior to enrollment. Locally advanced disease with recurrence after chemoradiation therapy (stage IIIB disease, specifically refers to patients with no curative options), is eligible to enroll. Prior adjuvant or neoadjuvant chemotherapy for early stage lung cancer is permitted if completed at least 6 months prior to initiating study treatment.
   • Measurable disease by CT or MRI per RECIST 1.1 criteria (Appendix 3); radiographic tumor assessment performed within 28 days before treatment.
     • Target lesions may be located in a previously irradiated field if there is documented (radiographic) disease progression in that site after the completion of radiation therapy.
   • Subjects are to have tumor tissue sample available at central lab for PD -L1 IHC testing during the screening period. Subjects can initiate therapy before the result of IHC testing Either a formalin-fixed, paraffin-embedded (FFPE) tissue block or unstained tumor tissue sections, with an associated pathology report, must be submitted for biomarker evaluation prior to treatment. The tumor tissue sample may be fresh or archival if obtained within 6 months prior to enrollment, and there can have been no systemic therapy (eg, adjuvant or neoadjuvant chemotherapy) given after the sample was obtained. Tissue must be a core needle biopsy, excisional or incisional biopsy. Fine needle biopsies or drainage of pleural effusions with cytospins are not considered adequate for biomarker review. Biopsies of bone lesions that do not have a soft tissue component or decalcified bone tumor samples are also not acceptable.
   • Prior palliative radiotherapy to non-CNS lesions must have been completed at least 2 weeks prior to treatment. Subjects with symptomatic tumor lesions at baseline that may require palliative radiotherapy within 4 weeks of first treatment are strongly encouraged to receive palliative radiotherapy prior to treatment.
   • Screening laboratory values must meet the following criteria (using CTCAE v4):
     • WBC≥2000/μL
     • Neutrophils ≥1500/μL
     • Platelets≥100 x 103/μL
     • Hemoglobin ≥9.0 g/dL
     • Serum creatinine ≥1.5 x ULN or calculated creatinine clearance ≥ 50 mL/min (using the Cockcroft Gault formula) Female CrCl = (140- age in years) x weight in kg x 0.85 72 x serum creatinine in mg/dL Male CrCl = (140- age in years) x weight in kg x 1.00 72 x serum creatinine in mg/dL
     • AST/ALT <=3.0 x ULN (<= 5 x ULN if liver metastases are present)
     • Total bilirubin <=1.5 x ULN except subjects with Gilbert Syndrome who must have a total bilirubin level < 3.0 mg/dL).

   Subject Re-enrollment: This study permits the re-enrollment of a subject who has discontinued the study as a pre-treatment failure (ie,, subject has not been treated). If re-enrolled, the subject must be re-consented.

   • Age and Reproductive Status
     • Males and Females, ages ≥18 years of age
     • Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of study drug.
     • Women must not be breastfeeding
     • WOCBP must agree to follow instructions for method(s) of contraception from the time of enrollment for the duration of treatment plus 5 half-lives of nivolumab (half-life up to 25 days) plus 30 days (duration of ovulatory cycle) for a total of 23 weeks post treatment completion. WOCBP must also agree to follow instructions for method(s) of contraception for the duration of treatment
     • Men who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with nivolumab plus 5 half-lives of nivolumab plus 90 days (duration of sperm turnover) for a total of 31 weeks post treatment completion.
     • Azoospermic males and WOCBP who are continuously not heterosexually active are exempt from contraceptive requirements. However they must still undergo pregnancy testing as described in these sections.

     Investigators shall counsel WOCBP and male subjects who are sexually active with WOCBP on the importance of pregnancy prevention and the implications of an unexpected pregnancy. Investigators shall advise WOCBP and male subjects who are sexually active with WOCBP on the use of highly effective methods of contraception. Highly effective methods of contraception have a failure rate of < 1% when used consistently and correctly. At a minimum, subjects must agree to use one highly effective OR one less effective method of contraception as listed below:

     • HIGHLY EFFECTIVE METHODS OF CONTRACEPTION

       Highly effective methods of contraception have a failure rate of < 1% when used consistently and correctly. WOCBP and female partners of male subjects, who are WOCBP, are expected to use one of the highly effective methods of contraception listed below. Male subjects must inform their female partners who are WOCBP of the contraceptive requirements of the protocol and are expected to adhere to using contraception with their partner. Contraception methods are as follows:

       1. Progestogen only hormonal contraception associated with inhibition of ovulation.
       2. Hormonal methods of contraception including oral contraceptive pills containing combined estrogen + progesterone, vaginal ring, injectables, implants and intrauterine devices (IUDs) such as Mirena®
       3. Nonhormonal IUDs, such as ParaGard®
       4. Bilateral tubal occlusion
       5. Vasectomised partner with documented azoospermia 90 days after procedure
          • Vasectomised partner is a highly effective birth control method provided that partner is the sole sexual partner of the WOCBP trial participant and that the vasectomized partner has received medical assessment of the surgical success.
       6. Intrauterine hormone-releasing system (IUS).
       7. Complete abstinence
          • Complete abstinence is defined as the complete avoidance of heterosexual intercourse (refer to Glossary of Terms)
          • Complete abstinence is an acceptable form of contraception for all study drugs and must be used throughout the duration of the study treatment (plus 5 half-lives of the investigational drug plus 30 days).
          • It is not necessary to use any other method of contraception when complete abstinence is elected.
          • Subjects who choose complete abstinence must continue to have pregnancy tests, as specified in Section 6.4.
          • Acceptable alternate methods of highly effective contraception must be discussed in the event that the subject chooses to forego complete abstinence.
          • The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the subject.
   • LESS EFFECTIVE METHODS OF CONTRACEPTION
     1. Diaphragm with spermicide
     2. Cervical cap with spermicide
     3. Vaginal sponge with spermicide
     4. Male or female condom with or without spermicide*
     5. Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the primary mode of action.

     * A male and a female condom must not be used together.

   • UNACCEPTABLE METHODS OF CONTRACEPTION
     1. Periodic abstinence (calendar, symptothermal, post-ovulation methods)
     2. Withdrawal (coitus interruptus)
     3. Spermicide only
     4. Lactation amenorrhea method (LAM)

Exclusion Criteria

1. Target Disease Exceptions
   • Subjects with known EGFR mutations which are sensitive to available targeted inhibitor therapy (including, but not limited to, deletions in exon 19 and exon 21 [L858R] substitution mutations) are excluded. All subjects with non-squamous histology must have been tested for EGFR mutation status. EGFR test is to be done locally. Use of an FDA-approved test (PCR based assay) is strongly encouraged. Tests other than PCR or next generation sequencing will be requested to repeat using PCR or next generation sequencing based methods. Subjects of non-squamous histology with unknown or indeterminate EGFR status are excluded.
   • Subjects with known ALK translocations which are sensitive to available targeted inhibitor therapy are excluded. If tested, use of an FDA-approved test is strongly encouraged. Subjects with unknown or indeterminate ALK status may be enrolled.
   • Subjects with untreated CNS metastases are excluded. Subjects are eligible if CNS metastases are adequately treated and subjects are neurologically returned to baseline (except for residual signs or symptoms related to the CNS treatment) for at least 2 weeks prior to first treatment. In addition, subjects must be either off corticosteroids, or on a stable or decreasing dose of <=10 mg daily prednisone (or equivalent) for at least 2 weeks prior to first treatment.
   • Subjects with carcinomatous meningitis
2. Medical History and Concurrent Diseases
   • Subjects must have recovered from the effects of major surgery or significant traumatic injury at least 14 days before first treatment.
   • Subjects with previous malignancies (except non-melanoma skin cancers, and in situ cancers such as the following: bladder, gastric, colon, cervical/dysplasia, melanoma, or breast) are excluded unless a complete remission was achieved at least 2 years prior to first treatment and no additional therapy is required or anticipated to be required during the study period.
   • Other active malignancy requiring concurrent intervention.
   • Subjects with an active, known or suspected autoimmune disease. Subjects with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
   • Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of first treatment. Inhaled or topical steroids, and adrenal replacement steroid > 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease.
   • Subjects with interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity.
   • Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
   • Known medical condition that, in the investigator's opinion, would increase the risk associated with study participation or study drug administration or interfere with the interpretation of safety results.
   • Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways
3. Physical and Laboratory Test Findings
   • Any positive test for hepatitis B virus or hepatitis C virus indicating acute or chronic infection
   • Subjects with ≥ Grade 2 peripheral neuropathy
4. Allergies and Adverse Drug Reaction
   • History of allergy or hypersensitivity to study drug components
5. Other Exclusion Criteria
   • Prisoners or subjects who are involuntarily incarcerated. (Note: under certain specific circumstances a person who has been imprisoned may be included or permitted to continue as a subject. Strict conditions apply and Bristol-Myers Squibb approval is required.
   • Subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness
   • Any other serious or uncontrolled medical disorder, active infection, physical exam finding, laboratory finding, altered mental status, or psychiatric condition that, in the opinion of the investigator, would limit a subject's ability to comply with the study requirements, substantially increase risk to the subject, or impact the interpretability of study results
   • Subjects with a history of screen failure to any anti-PD-1 or anti-PD-L1 antibody clinical trial due to PD-L1 negative status.