A Study to Evaluate Sotigalimab (APX005M) in Subjects With Unresectable or Metastatic Melanoma

A Phase II Multicenter, Open-label Study to Evaluate the Safety and Efficacy of the CD40 Agonistic Antibody Sotigalimab (APX005M) With or Without Stereotactic Body Radiation Therapy in Adults With Unresectable or Metastatic Melanoma

This is a multicenter, open label, Phase 2 study, with 3 parallel cohorts. The aim of the study is to evaluate the efficacy of sotigalimab (APX005M) administered at 2 different schedules to adult participants with unresectable or metastatic melanoma. Participants who have not received prior immunotherapy will be alternately assigned to 1 of 2 cohorts with different sotigalimab administration schedules as long as both are open for enrollment. Participants who have failed any number of prior lines of therapy will be assigned to a 3rd cohort of sotigalimab in combination with radiation therapy.

This is a multicenter, open label, Phase 2 study, with 3 parallel cohorts. The aim of the study is to evaluate the efficacy of Sotigalimab administered at 2 different schedules to adult participants with unresectable or metastatic melanoma who have not received prior immunotherapy. Enrolled participants will be alternately assigned to one of the following 2 cohorts (groups) as long as both cohorts are open.

Cohort 1: APX005M administered IV at 0.3 mg/kg every 3 weeks (21-day cycle) Cohort 2: APX005M administered IV at 0.3 mg/kg every 2 weeks (14-day cycle) Sotigalimab in combination with stereotactic body radiation therapy (SBRT) in adults with unresectable or metastatic melanoma who have failed any number of prior lines of therapy will be assigned to Cohort 3: Sotigalimab administered IV at 0.3 mg/kg in combination with radiation therapy every 2 weeks (14 day cycle) up to 16 weeks followed by sotigalimab administered IV at 0.3 mg/kg every 2 weeks (14-day cycle).

Primary Objective

• Evaluate the overall response rate (ORR) by RECIST 1.1 measurements in each of the cohorts.

Secondary Objectives

• Evaluate the safety of sotigalimab alone or in combination with radiation therapy in each cohort
• Evaluate ORR by modified RECIST 1.1 for immune-based therapeutics (iRECIST) in each cohort
• Evaluate median duration of response (DOR) in each cohort

Inclusion Criteria:

1. Histologically or cytologically confirmed unresectable or metastatic melanoma

2. Subjects with BRAF activating mutation must have received a BRAF inhibitor and/or MEK inhibitor regimen prior to study entry

3. Signed written informed consent approved by the relevant local ethics committee(s)

4. Male or female ≥18 years old at time of consent

5. Measurable disease by RECIST 1.1

   a. For Cohort 3 only, subjects must have at least 3 measurable target lesions

6. ECOG performance status of 0 or 1

7. Resolution of all disease or prior treatment-related toxicities to Grade ≤1, with the exception of alopecia, Grade 2 neuropathy and laboratory abnormalities (parameters below apply). If subject received major surgery or radiation therapy of >30 Gy, they must have recovered from the toxicity and/or complications from the intervention

8. Adequate organ function within 14 days prior to first dose of investigational therapy(ies):

   1. WBC ≥2 x 109/L in absence of growth factor support
   2. ANC ≥1.0 x 109/L in absence of growth factor support
   3. Platelet count ≥100 x 109/L
   4. Hemoglobin ≥9 g/dL
   5. Serum creatinine ≤1.5 mg/dL
   6. Calculated (using the formula of local laboratory) or creatinine clearance ≥60 mL/min
   7. AST and ALT ≤2.5 x ULN
   8. Total bilirubin ≤1.5 x ULN, or direct bilirubin ≤ULN with total bilirubin levels >1.5 x ULN
   9. INR or PT ≤1.5 x ULN unless receiving anticoag therapy PT or PTT is within therap, range
   10. aPTT ≤1.5 x ULN unless receiving anticoag therapy PT or PTT is within therap range

9. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test within the 7 days prior to first dose of investigational therapy(ies) and a negative urine pregnancy test within the 3 days prior to first dose of investigational therapy(ies), or a negative serum pregnancy test within the 3 days prior to first dose of investigational therapy(ies)

10. Women of childbearing potential must agree to follow instructions for method(s) of contraception for the duration of study treatment and 5 months after the last dose of investigational therapy(ies). Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of study treatment and 7 months after the last dose of investigational therapy(ies)

11. Available archived or fresh tumor tissue sample for biomarker analysis. Cohort 3, only available archived tissue is required.

12. For subjects that consent to collection of tumor biopsies at study entry and before the first scheduled tumor assessment, primary or metastatic tumor that can be safely biopsied. Up to 18 subjects (6 subjects within each cohort) should consent to fresh core biopsies.

Exclusion Criteria:

1. Prior Therapy:

   1. Cohorts 1 and 2 only: Previous exposure to any immunomodulatory agent (such as CTLA-4, PD-1/PD-L1, IDO inhibitors, interferon, CD40 agonist etc.).
   2. Cohort 3 only: Prior therapy with a CD40 agonist. Any number of prior lines of therapy are eligible. A minimum washout period of 21 days from last line of therapy until investigational therapy(ies) administration should be observed.

2. Second malignancy (solid or hematologic) within the past 3 years except locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast

3. Active, known, clinically serious infections (≥ Grade 2 according to NCI-CTCAE v4.03) within the 14 days prior to first dose of investigational therapy(ies)

4. Use of systemic corticosteroids or other systemic immunosuppressive drugs within 28 days prior to first dose of investigational therapy(ies) (except inhaled corticosteroids)

   a. The use of physiologic doses of corticosteroids may be approved /w consultation Medical Monitor (or designee)

5. Major surgery within 4 weeks prior to first dose of sotigalimab

6. Concurrent treatment with any anticancer agent and palliative radiation, unless approved by MM (or designee)

7. History of allogeneic bone marrow transplantation

8. Active, known or suspected autoimmune disease

9. Active autoimmune disease that has required systemic treatment in past 2 years (i.e with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Subjects with Type 1 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.

10. History of (non-infectious) pneumonitis that required corticosteroids or current pneumonitis

11. History of interstitial lung disease

12. History of sensitivity or allergy to mAbs or IgG

13. Congestive heart failure (New York Heart Association Class III to IV), symptomatic ischemia, conduction abnormalities uncontrolled by conventional intervention, or myocardial infarction within 6 months prior to the first dose of investigational therapy(ies)

14. History of any thromboembolic event within 3 months prior to first dose of investigational therapy(ies) or active coagulopathy

15. Known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with untreated brain metastases ≤3mm that are asymptomatic, do not have significant edema, cause shift, and do not require steroids or anti-seizure medications are eligible after discussion with the Medical Monitor. Lesions of any size in posterior fossa are excluded. Subjects with previously treated brain metastases may participate provided they are stable after treatment (without evidence of progression by imaging for at least 4 weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using corticosteroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability

16. Known human immunodeficiency virus (HIV), hepatitis B or hepatitis C infection

17. Has received a live (attenuated) vaccine within 30 days prior to the first dose of investigational therapy(ies). Seasonal flu vaccines that do not contain live virus and COVID 19 vaccines are permitted (see Section 3.2.3.4)

18. Has participated in another clinical trial of an investigational drug (or a medical device) within 30 days of study enrollment

19. Pregnant, breastfeeding, or unwilling to practice birth control during participation in the study

20. Any clinically significant psychiatric, social, or medical condition that, in the opinion of the Investigator, could increase subject's risk, interfere with protocol adherence, or affect a subject's ability to give informed consent.