Study of DF6215 in Patients With Advanced Solid Tumors

Inclusion

• Cytokine therapy (except for erythropoietin)
• For combination basket cohorts: received any prior immunotherapy and was discontinued from that treatment due to a Grade 3 or higher irAE (except endocrine disorders that can be treated with replacement therapy) or was discontinued from that treatment due to Grade 2 myocarditis or recurrent Grade 2 pneumonitis.
• Persisting toxicity related to a prior therapeutic agent \> Grade 1 as defined by NCI CTCAE v5.0 (however, ≤ Grade 2 alopecia, ≤ Grade 2 endocrinopathies, and ≤ Grade 2 sensory neuropathy are acceptable).
• Additional Exclusion Criteria apply to each cohort.
• Effective Contraception.
• Immune therapy
• Receipt of any organ transplant, including autologous or allogeneic stem-cell transplantation.
• Patients must not have received aldesleukin or any other experimental IL-2 based drug, including intralesional administration.
• Patients receiving any of the following concurrent anticancer treatments or investigational drugs within 28 days before the start of the study drug(s), or within 5 half-lives of the previous therapeutic agent (if known), whichever is shorter:
• Preexisting autoimmune disease (except vitiligo) needing treatment with systemic immunosuppressive agents for more than 28 days within the last 3 years, or clinically relevant immunodeficiencies (eg, dysgammaglobulinemia or congenital immunodeficiencies). Patients with a history of immune related endocrinopathies (eg, hypothyroidism, hyperthyroidism, and type 1 diabetes mellitus) that are stable on hormone replacement therapy are eligible for this study.
• History of myocardial infarction within 6 months before the first dose of study drug(s)
• Patients with known HIV infection are excluded unless they meet the following criteria:
• Adequate renal function.
• CNS lesions are asymptomatic and previously treated
• Additional Inclusion Criteria apply to each cohort.Key Exclusion Criteria
• Pregnant or lactating.
• Grade 3 or 4 treatment-related toxicity during an anti-PD-1 or anti-PD-L1 treatment (excluding Grade 3 or 4 immune-related endocrinopathies adequately controlled with hormone replacement therapy).
• Patients who have received a live or live-attenuated vaccine within 30 days before the first dose of study drug. Administration of killed vaccines is allowed.
• A clinically relevant abnormality on the electrocardiogram (ECG)
• Patients with history of CAD must have a normal stress test (eg, thallium or technetium-99m sestamibi) and be cleared to participate in the study.
• A heart rate of \< 50 or \> 100 bpm at rest on screening ECG
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Congenital long QT syndrome or a prolonged QTc mean on screening ECG
• Patient does not require ongoing daily steroid treatment for replacement for adrenal insufficiency (except ≤ 10 mg prednisone \[or equivalent\]) for at least 14 days before the first dose of study drug
• For combination basket cohorts: received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or coinhibitory T-cell receptor (eg, CTLA-4, OX 40, CD137).
• Requiring supplementary oxygen therapy.
• An estimated life expectancy of ≥ 3 months.
• A history of heart failure, congestive heart failure, cardiomyopathy, uncontrolled hypokalemia, hypomagnesemia, or hypoglycemia; any evidence of conduction abnormality (eg, increased QRS complex)
• Received sotalol within 10 days of the first dose of study drug(s), or received a medication known to prolong the ECG QT interval within 14 days of the first dose of study drug(s)
• Normal pulmonary function.
• Known severe hypersensitivity reactions to mAbs (≥ Grade 3 as defined by NCI-CTCAE v5.0), any history of anaphylaxis, or uncontrolled asthma (ie, 3 or more features of partly controlled asthma).
• Significant acute or chronic hepatitis B virus (HBV), hepatitis C virus (HCV) infection during the screening window, as well as historic positive for human immunodeficiency virus (HIV) or clinically significant active infections that render the patient ineligible for study treatment as determined by the treating investigator.
• Major surgery (excluding prior diagnostic biopsy)
• Medically uncontrolled angina pectoris
• Imaging demonstrates stable disease 28 days after last treatment
• An implantable pacemaker or automatic implantable cardioverter-defibrillator
• Note that short-term administration of systemic steroids (eg, for allergic reactions or the management of irAEs) and physiologic dose steroids (≤ 10 mg prednisone, or equivalent) for those with treated brain metastases are allowed. Patients receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of study drug(s) will be excluded.
• Adequate hepatic function.
• Key Inclusion Criteria
• Patients on antiretroviral therapy (ART) must have achieved and maintained virologic suppression defined as confirmed HIV RNA level below 50 or the LLOQ (below the limit of detection) using the locally available assay at the time of screening and for at least 12 weeks before screening and agree to continue ART throughout the study
• Patients with known history of neurologic conditions, cerebrovascular accident, or seizures.
• Clinically relevant coronary artery disease (CAD) or uncontrolled congestive heart failure
• Patients with brain metastases are excluded, unless all of the following criteria are met:
• Patients receiving chemotherapy, radiotherapy (other than palliative bone-directed radiotherapy), major surgery, or receiving another systemic anticancer therapeutic agent within 28 days before the start of study drug(s) or within 5 half-lives of the previous therapeutic agent (if known), whichever is shorter.
• Known alcohol or drug abuse.
• Primary tumor site of nasopharynx (any histology).
• Concurrent systemic therapy with steroids or other immunosuppressive agents.
• Severe hypersensitivity (≥ Grade 3) to study drugs and/or any of their excipients.
• Patients with a known medical history of keratitis, ulcerative keratitis, or corneal perforation.
• QTc \> 470 msec for women and \> 450 msec for men
• Grade 2 treatment-related toxicity that impacted either the lungs, the nervous system, or the cardiac system, during an anti-PD-1 or anti-PD-L1 treatment (patients with a history of Grade 2 peripheral neuropathy, or paresthesia, not related to anti-PD-1 or anti-PD-L1 treatments are eligible).
• Cytoreductive therapy
• A history of risk factors for ventricular tachycardia, torsades de pointes, fainting, unexplained loss of consciousness, or convulsions
• Patients in certain cohorts with prior anti-PD-1 and anti-PD-L1 treatment are eligible for the study, unless they have experienced any of the following:
• Any of the following cardiac abnormalities:
• Must have CD4+ T-cell (CD4+) counts ≥ 350 cells/μL at the time of screening, and
• Severe dyspnea at rest due to complications of advanced malignancy.
• Note: ≤ 2 weeks of palliative radiotherapy for non-CNS disease is permitted. The last radiotherapy treatment must have been performed at least 7 days before the first dose of study drug.
• Adequate hematological function.
• Legal incapacity or limited legal capacity.
• All other significant diseases (eg, inflammatory bowel disease) which, in the opinion of the Investigator, might impair the patient's ability to participate.
• Radiotherapy (except for palliative bone-directed radiotherapy)
• Bisphosphonate or denosumab initiated within 14 days of the first dose of study drug(s)

Exclusion

Exclusion criteria not yet provided.