Dose Escalation of DF6002 in Patients With Advanced Solid Tumors, and Expansion in Selected Indications
Dose Escalation of DF6002 in Patients With Advanced 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.
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.