A Safety and Efficacy Study of CC-90011 in Combination With Nivolumab in Subjects With Advanced Cancers

A Phase 2, Multicenter, Open-label, Multi-cohort Study to Assess Safety and Efficacy of CC-90011 in Combination With Nivolumab in Subjects With Advanced Cancers

This is a Phase 2, multicenter, open-label, multi-cohort study to assess safety and efficacy of CC-90011 in combination with nivolumab in subjects with small cell lung cancer or squamous non-small cell lung cancer who have progressed after 1 or 2 lines of therapies.

The primary objectives of the study are to evaluate the overall response rate of subjects treated with CC-90011 in combination with nivolumab in three cohorts:

• Cohort A: SCLC in ICI naïve subjects
• Cohort B: SCLC in ICI progressor subjects
• Cohort C: sqNSCLC in ICI progressor subjects Overall response rate is defined as the proportion of subjects in the treated population who had complete response (CR) or partial response (PR) as assessed by Investigator review per RECIST v1.1.

In Cohort A, expected ORR for nivolumab monotherapy is 14% while target ORR is 30%. To achieve at least 80% power with one-sided type 1 error 0.1, 39 subjects will be enrolled according to a 2-stage group sequential design based on a binomial test. In stage 1, 12 subjects will be enrolled and treated with CC-90011 in combination with nivolumab. If there are 2 or more subjects responding, Cohort A will continue to enroll an additional 27 subjects. If 1 or less subjects respond in stage 1, Cohort A will stop for futility.

In Cohort B and C, expected ORR for nivolumab monotherapy is 5% while target ORR is 15%. To achieve at least 80% power with one-sided type 1 error 0.1, 48 subjects will be enrolled according to a 2-stage group sequential design based on a binomial test. In stage 1, 14 subjects will be enrolled and treated with CC-90011 in combination with nivolumab. If there are 1 or more subjects responding, Cohort B and C will continue to enroll an additional 34 subjects each. If 0 subjects respond in stage 1, Cohort B and C will stop for futility.

Inclusion Criteria:

Subjects must satisfy the following criteria to be enrolled in the study:

1. Subject is ≥ 18 years of age at the time of signing the informed consent form (ICF).

2. Subject with histological or cytological confirmation of extensive stage Small Cell Lung Cancer (ES SCLC) or Stage IIIb or IV squamous Non-Small Cell Lung Cancer (sqNSCLC)

3. Subject has received 1 or 2 prior lines of therapies, defined as:

   1. Cohort A (SCLC, Immune Checkpoint Inhibitor naïve):

      • At least 1 prior treatment including a platinum-based chemotherapy doublet
      • A minimum of 3 cycles of platinum-based chemotherapy in first line treatment, unless stopped at 2 cycles due to treatment-related toxicity

   2. Cohort B (SCLC, ICI progressors):

      • At least 1 prior first or second line treatment includes an ICI
      • If treatment includes an ICI as maintenance therapy, at least 1 cycle of ICI in maintenance should have been completed
      • At least 1 prior treatment including a platinum-based chemotherapy doublet
      • A minimum of 3 cycles of platinum-based chemotherapy, with or without ICI, in first line treatment, unless stopped at 2 cycles due to treatment-related toxicity
      • Subject must have progressed during ICI therapy, defined as unequivocal progression on or within 3 months of the last dose of ICI therapy (if no subsequent therapy)

   3. Cohort C (sqNSCLC, ICI progressors):

      • At least 1 prior first or second line treatment includes an ICI
      • If treatment includes an ICI as maintenance therapy, at least 1 cycle of ICI in maintenance should have been completed
      • At least 1 prior treatment including a platinum-based chemotherapy doublet
      • A minimum of 3 cycles of platinum-based chemotherapy, with or without an ICI, in first line treatment, unless stopped at 2 cycles due to treatment-related toxicity
      • Subject must have progressed during ICI therapy, defined as unequivocal progression on or within 3 months of the last dose of ICI therapy (if no subsequent therapy)

4. Subject has progressed at the last line of therapy.

5. Subject has a measurable disease defined by RECIST v1.1.

6. Subject agrees to provide a tumor biopsy from primary or metastatic site prior to first dose and at a pre-specified timepoint during treatment. Core biopsy is required however, in the event a core biopsy may not otherwise be feasible in the opinion of the treating physician, an endobronchial ultrasound-guided fine needle aspirate [EBUS-FNA]) biopsy, using the largest gauge needle, may be performed instead.

7. Subject has ECOG Performance Status of 0 to 1.

8. Subject must have the following laboratory values:

   1. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
   2. Hemoglobin (Hgb) ≥ 9 g/dL (one-time blood transfusion is allowed)
   3. Platelet (Plt) Count ≥ 150 x 109/L
   4. White blood cells (WBC) ≥ 2 x 109L
   5. Serum AST/serum glutamic oxaloacetic transaminase (SGOT) or ALT/serum glutamic pyruvic transaminase (SGPT) ≤ 3 x upper limit of normal (ULN) or ≤ 5 x ULN if presence of liver metastases
   6. Total serum bilirubin ≤ 1.5 x ULN (≤ 3 x ULN, if Gilbert's syndrome or if indirect bilirubin concentrations are suggestive of extrahepatic source of the elevation)
   7. Creatinine clearance (CrCl) ≥ 60 mL/minute based on Cockcroft-Gault or modification of diet in renal disease (MDRD) or ≥ 60 mL/min/1.73 m2

Exclusion Criteria:

The presence of any of the following will exclude a subject from enrollment:

1. Subject has not recovered to Grade 2 or lower clinically significant toxicities related to the prior therapy (alopecia excluded).

2. Subject has received prior LSD1 therapies.

3. Subject has a history of severe hypersensitivity reactions to other monoclonal antibodies

4. Subject with symptomatic and untreated or unstable central nervous system (CNS) metastases.

   1. Subject has recently been treated with whole brain radiation or stereotactic radiosurgery for CNS metastases must have completed therapy at least 2 weeks prior to Cycle 1 Day 1 and has a follow-up brain computed tomography (CT) or magnetic resonance imaging (MRI) demonstrating either stable or improving metastases 2 or more weeks after completion of radiotherapy.
   2. Subject must be asymptomatic and off steroids or on stable dose of steroids for at least 2 weeks (≤ 10 mg daily prednisone or equivalent) prior to first dose.

5. Subject has persistent diarrhea due to a malabsorptive syndrome (such as celiac sprue or inflammatory bowel disease) ≥ NCI CTCAE Grade 2, despite medical management), or any other significant gastrointestinal (GI) disorder that could affect the absorption of the study treatments.

6. Subject with symptomatic or uncontrolled ulcers (gastric or duodenal), particularly those with a history of and/or risk of perforation and GI tract hemorrhages.

7. Subject with any hemorrhage/bleeding event > NCI CTCAE Grade 2 or haemoptysis > 1 teaspoon within 4 weeks prior to the first dose.

8. Subject has any of the following cardiovascular criteria:

   1. Evidence of acute or ongoing cardiac ischemia
   2. Current symptomatic pulmonary embolism
   3. Unstable angina pectoris or myocardial infarction ≤ 6 months prior to enrollment
   4. Heart failure of New York Heart Association Classification III or IV ≤ 6 months prior to enrollment
   5. Persistent or clinically meaningful ventricular arrhythmias prior to enrollment
   6. Cerebral vascular accident or transient ischemic attack ≤ 6 months prior to enrollment
   7. QT corrected based on Fridericia's equation (QTcF) ≥ 450 milliseconds (msec) on Screening ECG, a baseline prolongation of QTcF interval ≥ 450 msec (NCI CTCAE Grade ≥ 2)
   8. A history of additional risk factors for Torsades de pointes (TdP) (eg, heart failure, hypokalemia, family history of Long QT Syndrome)
   9. Uncontrolled hypertension (blood pressure ≥ 160/95 mm Hg)

9. Subject has known human immunodeficiency virus (HIV) infection.

10. Subject has known chronic active hepatitis B or C virus (HBV, HCV) infection.

    1. Subject who is seropositive due to HBV vaccination is eligible.
    2. Subject who has no active viral infection and is under adequate prophylaxis against HBV reactivation is eligible.

11. Subject has any other malignancy within 2 years prior to enrollment, with the exception of adequately treated in-situ bladder cancer, in-situ carcinoma of the cervix, uteri, nonmelanomatous skin cancer, ductal in situ breast carcinoma, thyroid cancer, or early stage prostate cancer (all treatment of which should have been completed 6 months prior to enrollment).

12. Subject has medical conditions requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone or equivalent) or other immunosuppressive medications within 14 days of enrollment.

    1. A brief (≤ 7 days) course of corticosteroids for prophylaxis (eg, contrast dye allergy) or for treatment of nonautoimmune conditions (eg, delayed-type hypersensitivity reaction caused by contact allergen) is permitted.
    2. Adrenal replacement steroid doses > 10 mg daily prednisone or equivalent are permitted in the absence of active autoimmune disease.
    3. Topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic absorption) are permitted.

13. Subject has active autoimmune diseases or history of autoimmune diseases that may relapse. Subjects with the following diseases are allowed to be enrolled after further screening: type I diabetes, hypothyroidism managed with hormone replacement therapy only, skin diseases not requiring systemic treatment (such as vitiligo, psoriasis, or alopecia), or diseases not expected to recur in the absence of external triggering factors.

14. Subject is pregnant or nursing.

15. Subject has a history of persistent skin rash ≥ NCI CTCAE Grade 2 related to prior ICI therapy.

16. Subject has organ transplant history, including allogeneic stem cell transplant.

17. Subject has interstitial lung disease history.

18. Subject has received a live/attenuated vaccine within 30 days of first dose.

19. Subject has previous SARS-CoV-2 infection either suspected or confirmed within 4 weeks prior to screening.

    1. Acute symptoms must have resolved and based on Investigator assessment in consultation with the Medical Monitor, there are no sequelae that would place the subject at a higher risk of receiving investigational treatment.