The Study of NC318 Alone or in Combination With Pembrolizumab in Patients With Advanced Non-small Cell Lung Cancer

This is a non-randomized, three-arm trial.

Arm 1a and 1b will enroll patients with advanced NSCLC regardless of tumor PD-L1 expression who have experienced disease progression on or after PD-1 axis inhibitor therapy, given alone or in combination with other systemic anti-cancer therapy. Patients will be assigned to arm 1a or 1b at the discretion of the treating physician. Patients on arm 1a will receive NC318 alone; those on arm 1b, combination therapy with NC318 and pembrolizumab.

Arm 1a will be based on a Simon two-stage minimax design. In the first stage, 18 patients will be accrued. If tumor response per RECIST v1.1 is achieved in 2 or fewer patients, arm 1a will be closed to further enrollment. If tumor response is demonstrated in 3 or more patients, then 25 additional patients will be accrued (stage 2), for a total of 43 patients.

Arm 1b arm will start with a safety run-in portion consisting of 6 patients (see 4.1.1). If deemed safe, arm 1b will continue to accrue and follow the Simon two-stage design used in arm 1a. Patients in the run-in portion will be included in stage 1 of the Simon two-stage design.

Arm 2 will enroll patients with advanced NSCLC and tumor PD-L1 expression less than 50% who are naïve to PD-1 axis inhibitor therapy. Patients on arm 2 will receive combination therapy with NC318 and pembrolizumab. Arm 2 will also start with a safety run-in portion identical to that of arm 1b (see 4.1.1). If deemed safe, accrual will continue following a Simon two-stage minimax design. In the first stage, 19 patients will be accrued. If tumor response per RECIST v1.1 is achieved in 3 or fewer patients, arm 2 will be closed to further enrollment. If tumor response is demonstrated in 4 or more patients, then 36 additional patients will be accrued (stage 2), for a total of 54 patients. Patients in the run-in portion will be included in stage 1 of the Simon two-stage design.

Inclusion Criteria:

• Age ≥18 years
• Histologically or cytologically documented, locally advanced or metastatic (i.e., Stage IIIB not eligible for definitive chemoradiotherapy, Stage IV, or recurrent) NSCLC (per the American Joint Committee /AJCC staging system)
• ECOG performance status of 0 to 1
• Measurable disease, as defined by RECIST v1.1. Previously irradiated lesions can be counted as target lesions if clearly progressing after radiation.
• Arm 1a and 1b: Prior PD-1 axis inhibitor therapy (anti-PD-1 or anti-PD-L1, e.g. nivolumab, pembrolizumab, atezolizumab, durvalumab, avelumab) either alone or in combination 9 with other systemic agents, with documented progressive disease. - Arm 2: PD-L1 expression of less than 50 percent (PD-1 axis inhibitor therapy naïve)
• Patients with NSCLC known to harbor an ALK rearrangement, ROS1 rearrangement, EGFR mutation or BRAF mutation known to be sensitive to FDA approved tyrosine kinase inhibitors (TKIs), are only eligible after experiencing disease progression (during or after treatment) or intolerance to respective TKI:

  c. Patients with TKI treated EGFR mutant NSCLC harboring the secondary EGFR T790M tumor must have received prior osimertinib.

  d. Patients with crizotinib treated ALK rearranged NSCLC must have received a next generation ALK inhibitor (e.g. ceritinib, alectinib, brigatinib or lorlatinib).

• At least one tumor amenable to incisional, excisional, core or forceps (transbronchial) biopsy. Patients must be willing to undergo a tumor biopsy before starting trial therapy and at the time of disease progression.
• For female patients of childbearing potential and male patients with partners of childbearing potential, agreement (by patient and/or partner) to use a highly effective form(s) of contraception (i.e., one that results in a low failure rate [<1% per year] when used consistently and correctly) and to continue its use for 6 months after the last dose of trial therapy. Highly effective contraception is one with a failure rate of <0.1%. Birth control pills on their own do not achieve that rate.
  • Women of childbearing potential must have a negative pregnancy test (serum or urine) within 72 hours of the start of study drug administration
  • Women who have recently given birth must no longer be breastfeeding
• Adequate hematologic and end-organ function, defined by the following laboratory results obtained within 14 days prior to the first study treatment:
• Neutrophils ≥1000 cells/μL (without granulocyte colony-stimulating factor support within 2 weeks prior to Cycle 1, Day 1)
• Platelets ≥75,000/μL (transfusion to achieve this level is not permitted within 2 weeks of the first study drug administration)
• Hemoglobin ≥8.0 g/dL
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3 x institutional upper limit of normal (ULN) with the following exceptions: Patients with documented liver metastases: AST and/or ALT≤5 x ULN
• Serum bilirubin ≤1.5 x ULN (Patients with known Gilbert disease who have serum bilirubin level ≤3 x ULN may be enrolled)
• Serum creatinine ≤1.5 x ULN or creatinine clearance ≥50 mL/min

Exclusion Criteria:

• Has an active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents. Subjects with vitiligo or resolved childhood asthma/atopy would be an exception to this rule. Subjects who require intermittent use of inhaled steroids or local steroid injections would not be excluded from 10 the study. Subjects with hypothyroidism stable on hormone replacement, or psoriasis not requiring systemic therapy (within the past 3 years) will not be excluded from the study. - Interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity
• History of non-infectious pneumonitis requiring steroids or current pneumonitis
• Subjects must not have a history of life-threatening toxicity related to prior anti-PD-1 axis therapy:

  • Subjects with history of anti-PD-1 axis therapy toxicities that are unlikely to recur with standard countermeasures (e.g., hormone replacement after adrenal crisis) are eligible.

• Symptomatic or untreated CNS metastases. Patients with a history of treated asymptomatic CNS metastases are eligible, provided they meet all of the following criteria:

  d. No evidence of interim progression between the completion of CNS-directed therapy and the start of trial therapy e. No ongoing requirement for dexamethasone as therapy for CNS disease; anticonvulsants at a stable dose are allowed.

  f. Completed stereotactic radiosurgery at least 1 week prior to Cycle 1, Day 1 or whole-brain radiation at least 2 weeks prior to Cycle 1, Day 1.

• History of leptomeningeal carcinomatosis
• Prior palliative radiotherapy outside the CNS within 2 weeks of the first dose of study drug
• Treatment with systemic immunosuppressive medications (including but not limited to, dexamethasone at doses > 2 mg daily (or equivalent dose of other corticosteroids), cyclophosphamide, tacrolimus, sirolimus, azathioprine, methotrexate, thalidomide, and antitumor necrosis factor [anti-TNF] agents) within 2 weeks prior to initiating trial therapy (Inhaled or topically applied steroids, and acute and chronic standard-dose NSAIDs are permitted. Replacement steroids are also permitted).
• Subjects must not have received vaccines containing live virus for prevention of infectious diseases within 12 weeks prior to the first dose of study drug.

  • The use of inactivated seasonal influenza vaccines (eg, Fluzone®) will be permitted on study without restriction

• Any approved systemic anti-cancer therapy, within 3 weeks prior to initiation of study treatment; the following exception is allowed:

  • TKIs approved for treatment of NSCLC discontinued > 7 days prior to Cycle 1, Day 1. The baseline scan must be obtained after discontinuation of prior TKIs

• Treatment with any other investigational agent or participation in another clinical trial with therapeutic intent within 21 days prior to enrollment; the following exceptions are allowed:

  • Unapproved/experimental TKIs discontinued 14 days prior to Cycle 1, Day 1

• Known infection with HIV, HBV or HCV. Patients with prior exposure to hepatitis, but no evidence of active or chronic infection, may be eligible

  • Subjects with positive hepatitis C antibody and negative quantitative hepatitis C by polymerase chain reaction are eligible 11

• Active systemic infection requiring systemic antibiotic treatment within 72 hours prior to first dose of study treatment
• Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, or psychiatric illness/social situations that would limit compliance with study requirements
• Major surgery or traumatic injury within 4 weeks of starting study drug
• Women who are pregnant or lactating
• Any underlying medical condition that in the Principal Investigator's opinion will make the administration of study drug hazardous to the patient or would obscure the interpretation of adverse events
• Grade 4 amylase or lipase elevation
• Arm 2: No prior PD-1 axis inhibitor therapy