A Study of the c-Kit Specific Antibody-Drug Conjugate NN3201 for Advanced and/or Metastatic Solid Tumors Known to Express c-Kit

The drug being tested in this study is called NN3201, a c-Kit targeting fully human monoclonal antibody-drug conjugate with MMAE, administered by IV. The study will be conducted in two parts, a dose escalation phase (Part A) followed by an expansion phase (Part B).

The patient population for the dose escalation phase (Part A) of the study will include patients with advanced and/or metastatic c-Kit-associated solid tumors including gastrointestinal stromal tumor (GIST), adenoid cystic carcinoma (ACC), uveal melanoma, neuroendocrine tumors (NET), and chromophobe and clear cell renal cell carcinomas (ChRCC and ccRCC). For Part A patients must have received treatment with imatinimb for GIST or be progressive/refractory, ineligible, or intolerant to available standard therapy (or subject declines standard therapy) for cKit-associated solid tumors (ACC, uveal melanoma, NET, ChRCC, or ccRCC). The primary objective of the dose escalation phase (Part A) is to determine the safety profile of NN3201 administered by IV, including the incidence and severity of adverse events (AEs), serious adverse events (SAEs), and dose-limited toxicities (DLTs) as well as the incidence of abnormal laboratory findings and abnormal vital signs. Part A will help determine the maximum tolerated dose (MTD) and/or the recommended dose(s) (RDEs) for the expansion phase (Part B).

Once a recommended dose has been determined in the escalation phase (Part A), the expansion phase (Part B) will assess the safety and efficacy of NN3201 when administered at 2 RDE dose levels to subjects in two indication-specific (GIST and SCLC) expansion cohorts and one basket cohort for c-Kit positive solid tumors (excluding GIST and SCLC). All cohorts in Part B will utilize the same eligibility criteria as in Part A.

Cohort B1 - GIST: up to 10 subjects with GIST will be enrolled at the MTD level (RDE1) and efficacy and safety as well as any available PK and PD data will be evaluated.

Cohort B2 - SCLC: up to 10 SCLC will be enrolled at 1 dose level below MTD (MTD-1/RDE2) and efficacy and safety as well as any available PK and PD data will be evaluated. The Scientific Review Committee (SRC) may decide to enroll and additional 10 subjects in SCLC subjects.

Cohort B3 - c-Kit-associated solid tumors: in this basket cohort, up to 10 subjects with any c-Kit-associated solid tumor (including ACC, uveal melanoma, NET, ChRCC, and ccRCC and excluding GIST and SCLC) will be enrolled.

The safety and tolerability of NN3201 administered intravenously (IV) at up to two RDEs in subjects with advanced and/or metastatic solid tumors is the primary objective for Part B.

Key Inclusion Criteria:

Subjects must meet the following criteria to be eligible for enrollment into the study:

• Histologically or cytologically confirmed locally advanced, metastatic, and/or unresectable GIST, SCLC, ACC, uveal melanoma, NET ChRCC or ccRCC.
• Subjects must have received the following treatment:

Part A (Dose Escalation):

i. Treatment with imatinib for GIST (at least one line of therapy with imatinib)

or

ii. Progressive/refractory, ineligible, or intolerant to available standard therapy (or subject declines standard therapy) for c-Kit-associated solid tumors (ACC, uveal melanoma, NET ChRCC or ccRCC)

Part B (Dose Expansion):

i. Treatment with imatinib for GIST (at least one line of therapy with imatinib) or

ii. Progressive/refractory, ineligible, or intolerant to available standard therapy (or subject declines standard therapy) for Extensive stage SCLC or

iii. Progressive/refractory, ineligible, or intolerant to available standard therapy (or subject declines standard therapy) for c-Kit-associated solid tumors (ACC, uveal melanoma, NET or ChRCC or ccRCC).

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Life expectancy ≥ 3 months before starting NN3201 in the opinion of the Investigator.
• Age ≥ 18 years.
• Laboratory values demonstrating adequately functioning kidney, liver and bone marrow (hematology).
• Adequate heart function as measured by ECHO/MUGA scan.
• Time between prior anticancer therapy including investigational agents and first dose of NN3201 as below:

• Cytotoxic chemotherapy - At least 21 days
• Non-cytotoxic chemotherapy (e.g., small molecule inhibitor) - At least 14 days
• Nitrosoureas - At least 6 weeks
• Monoclonal antibody(ies) - At least 28 days
• Radiotherapy - At least 14 days from local site radiation therapy
• Negative Serum/urine pregnancy test (for subjects of childbearing potential)
• All subjects of childbearing potential must agree to use contraception throughout the study and for additional 120 days after the last dose of assigned treatment. Subjects must refrain from donating sperm during the same period or Subjects who do not have childbearing potential are confirmed post-menopausal or sterile.
• Voluntary agreement to provide written informed consent and have willingness and ability to comply with all aspects of the protocol.

Key Exclusion Criteria:

• Has received prior therapy with a c-Kit agent (except GIST subjects).
• Known brain metastases that are untreated, symptomatic, or require therapy to control symptoms.
• 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 (inhaled corticosteroids are allowed).
• Any prior treatment-related (i.e., chemotherapy, immunotherapy, radiotherapy) clinically significant toxicities that have not resolved to Grade ≤ 1 or prior treatment-related toxicities that are clinically unstable and clinically significant at Study Entry, Day -2 to Cycle 1 Day 1.
• Major surgery within 30 days before the first dose of study drug treatment in Cycle 1 on Day 1 (port placement for venous access is not considered major surgery).
• Significant cardiovascular impairment.
• Significant screening electrocardiogram (ECG) abnormalities.
• Known active and clinically significant bacterial, fungal, or viral infection.
• Uncontrolled hypertension defined as systolic blood pressure ≥ 160mmHg and/or diastolic blood pressure ≥ 100mmHg, despite optimal medical management.
• Venous thrombosis or pulmonary embolism within the last 3 months prior to the screening.
• Ongoing or active infection requiring intravenous treatment with anti-infective therapy or systemic therapy and/or any identified active COVID-19 infection.
• Any other major illness that, in the Investigator's judgment, will substantially increase the risk associated with the subject's participation in this study.
• People who are pregnant or breastfeeding.

Other inclusion and exclusion criteria must also be met to be eligible to participate in this study.