A Phase 1/2, First-In-Human, Multi-Part, Open-Label, Multiple-Ascending Dose Study to Investigate the Safety, Tolerability, Pharmacokinetics, Biological, and Clinical Activity of DF6002 as a Monotherapy and in Combination With Nivolumab in Patients With Locally Advanced or Metastatic Solid Tumors, and Expansion in Selected Indications

This study is a Phase 1/2, open-label, dose-escalation study with a consecutive parallel-group efficacy expansion study, designed to determine the safety, tolerability, PK, pharmacodynamics, and preliminary anti-tumor activity of DF6002 as monotherapy and in combination with nivolumab.

The study consists of 3 parts:

Phase 1: Dose-escalation as a monotherapy using a 3+3 design, with Phase 1 Cohort Expansion.

Phase 1b: Dose-escalation as a combination with nivolumab using a 3+3 design, with Phase 1b Cohort Expansion.

Phase 2: Efficacy Expansion using a group sequential design.

In Phase 2, DF6002 will be evaluated as a monotherapy in the following indications:

Cohort 2A: Advanced (unresectable or metastatic) melanoma.

Cohort 2B: Advanced (unresectable or metastatic) non-small cell lung cancer (NSCLC).

In Phase 2, DF6002 will be evaluated in combination with nivolumab in the following indication:

Cohort 2C: Advanced (unresectable or metastatic) melanoma.

Cohort 2D: Advanced (unresectable or metastatic) NSCLC.

In each study phase, patients will receive DF6002 on Day 1 every 4 weeks (Q4W). Patients will receive DF6002 until confirmed progressive disease (PD), unacceptable toxicity (ie, dose-limiting toxicity [DLT]), or any reason for withdrawal from the study or Investigational Medicinal Product (IMP) occurs.

Inclusion Criteria (General Phase 1 and Phase 1b):

1. Male or female patients aged ≥ 18 years
2. Histologically or cytologically proven locally advanced or metastatic solid tumors, for which no standard therapy exists or standard therapy has failed among the following tumor types: melanoma, non-small cell lung cancer, small cell lung cancer, head and neck squamous cell, urothelial, gastric, esophageal, cervical, hepatocellular, merkel cell, cutaneous squamous cell carcinoma, renal cell, endometrial, triple-negative breast, ovarian, and prostate.
3. ECOG performance status of 0 or 1
4. Clinical or radiological evidence of disease
5. Adequate hematological, hepatic and renal function
6. Resolution of toxic effect(s) of prior anti-cancer therapy to ≤Grade 1 (Patients with ≤Grade 2 neuropathy, ≤Grade 2 endocrinopathy or ≤Grade 2 alopecia are exceptions)
7. Effective contraception for women of child-bearing potential as defined by World Health Organization guidelines for 1 "highly effective" method or 2 "effective" methods

Additional Phase 1 Monotherapy and Phase 1b Combination With Nivolumab Expansion Inclusion Criteria:

1. Has one of the following tumor types: melanoma, non-small cell lung cancer, or triple negative breast cancer
2. Agrees to undergo a pre-treatment biopsy and another biopsy while on treatment

Expansion Inclusion Criteria specific to Melanoma:

1. Histologically confirmed, unresectable Stage III or Stage IV melanoma, as specified in the American Joint Committee on Cancer staging system.
2. Participants with ocular or uveal melanoma are ineligible.
3. PD-L1 status must be documented if available.
4. BRAF (V600) mutation status must be known. Both BRAF-mutated and wild type participants are permitted in this cohort.
5. BRAF-mutated participants must have been treated with approved targeted therapies.
6. Must have documented progressive or recurrent disease on or after discontinuation of anti-PD-(L)1 therapy (administered as monotherapy or as part of a combination) as per RECIST 1.1 criteria:
7. Participants who received anti-PD-(L)1 in the adjuvant setting must have documented progressive or recurrent disease on or within 6 months of discontinuation of anti-PD-(L)1 therapy (administered as monotherapy or as part of a combination) as per RECIST 1.1 criteria.

Expansion Inclusion Criteria specific to NSCLC:

1. Histologically confirmed NSCLC meeting stage criteria for stage IIIB, stage IV, or recurrent disease.
2. Participants must have recurrent or progressive disease during or after platinum doublet-based chemotherapy or at least two prior lines of systemic therapy for advanced or metastatic disease OR Must have recurrent or progressive disease within 6 months after completing platinum-based chemotherapy for local disease.
3. Participants must have received and progressed on or after anti-PD-(L)1 therapy, if available.
4. Status for actionable mutations (e.g., EGFR, ALK, ROS1, RET, etc.) must be known (when testing is available as per country/region standard of care practices); participants with actionable mutations must have received and progressed on, have been intolerant to, or not be a candidate for, standard tyrosine kinase inhibitors (as available per country/region standard of care practices).

Expansion Inclusion Criteria specific to TNBC:

1. Histologically confirmed unresectable, locally advanced or metastatic triple negative breast cancer.PD-L1 status, HER2-negative, estrogen receptor-negative, and progesterone receptor-negative status must be evaluated by local institutions before enrolment per guidelines of the American Society of Clinical Oncology and the College of American Pathologists.
2. Patients must not have received an anti PD-1/PD-L1 for the treatment of the metastatic disease, but the administration of an anti PD-1/PD-L1 in the adjuvant setting is acceptable.
3. Patients must have received one line of chemotherapy for the treatment of their metastatic disease, and experience progression during or after that line of chemotherapy.
4. Patients must have not received more than one line of chemotherapy for the treatment of their unresectable, recurrent or metastatic disease.

Inclusion Criteria for Phase 2 (General)

1. Male or female patients aged ≥ 18 years.
2. ECOG performance status of 0 or 1
3. Clinical or radiological evidence of measurable disease.
4. Adequate hematological, hepatic and renal function.
5. Resolution of toxic effect(s) of prior anti-cancer therapy to ≤Grade 1. (Patients with ≤Grade 2 neuropathy, ≤Grade 2 endocrinopathy or ≤Grade 2 alopecia are exceptions.)
6. Participants must have received and progressed on or after anti-PD-(L)1 therapy.
7. Effective contraception for women of child-bearing potential as defined by World Health Organization guidelines for 1 "highly effective" method or 2 "effective" methods

Additional Inclusion Criteria for Phase 2 (Advanced Melanoma Patients)

1. Participants who received anti-PD-(L)1 in the advanced/metastatic setting, must have documented progressive or recurrent disease on or within 3 months of discontinuation of anti-PD-(L)1 therapy
2. Participants who received anti-PD-(L)1 in the adjuvant setting must have documented progressive or recurrent disease on or within 6 months of discontinuation of anti-PD-(L)1 therapy
3. Disease progression was confirmed at least 4 weeks after the initial diagnosis of disease progression while receiving an anti PD-1 antibody.
4. BRAF mutation status must be known and treated with approved targeted therapies.
5. Received a BRAF inhibitor if the tumor carries a BRAF activating mutation and progressed after the last line of treatment.
6. Participants with ocular or uveal melanoma are ineligible.
7. Confirmation of radiographic progression on prior anti-PD-(L)1 therapy is required with a scan confirming progression at least 4 weeks after the initial progression

Additional Inclusion Criteria for Phase 2 (Non-small Cell Lung Cancer)

1. Participants must have recurrent or progressive disease during or after platinum doublet-based chemotherapy or at least two prior lines of systemic therapy for advanced or metastatic disease OR must have recurrent or progressive disease within 6 months after completing platinum-based chemotherapy for local disease.
2. Status for actionable mutations must be known; participants with actionable mutations must have received and progressed on, have been intolerant to, or not be a candidate for, standard tyrosine kinase inhibitors

Exclusion Criteria for All Patients (All Phases)

1. Prior treatment with rhIL2 or any recombinant long acting drug containing an IL2 moiety.
2. Concurrent anticancer treatment (with the exception of palliative bone directed radiotherapy), immune therapy, or cytokine therapy (except for erythropoietin), major surgery (excluding prior diagnostic biopsy), concurrent systemic therapy with steroids or other immunosuppressive agents, or use of any investigational drug within 28 days before the start of study treatment.
3. Previous malignant disease other than the current target malignancy within the last 3 years, with the exception of basal or squamous cell carcinoma of the skin, localized prostate cancer or cervical carcinoma in situ.
4. Rapidly progressive disease.
5. Any Grade 2 and higher neurological or pulmonary toxicity during a treatment with an anti-PD-1 or PD-L1 agent administered as a monotherapy.
6. Active or history of central nervous system (CNS) metastases unless all of the following criteria are met:
   1. CNS lesions are asymptomatic and previously treated.
   2. Patient does not require ongoing steroid treatment daily for replacement for adrenal insufficiency.
   3. Imaging demonstrates stability of disease 28 days from last treatment for CNS metastases.
7. Receipt of any organ transplantation, autologous or allogeneic stem-cell transplantation.
8. Significant acute or chronic infections, or active or latent hepatitis B or active hepatitis C.
9. Preexisting autoimmune disease needing treatment with systemic immunosuppressive agents for more than 28 days within the last 3 years, clinically relevant immunodeficiencies, or fever within 7 days of Day 1.
10. Known severe hypersensitivity reactions to monoclonal antibodies and any history of anaphylaxis, or uncontrolled asthma
11. Serious cardiac illness or medical conditions.
12. History of life-threatening toxicity related to prior immune therapy except those that are unlikely to re-occur with standard countermeasures.