Study of Mogamulizumab + Nivolumab in Subjects w/Locally Advanced or Metastatic Solid Tumors

This is a multicenter, Phase 1/2 open-label, dose-finding and cohort expansion study of the anti-CCR4 antibody mogamulizumab in combination therapy with the anti-PD-1 antibody nivolumab in adult subjects with locally advanced or metastatic solid tumors.

Phase 1 will identify the maximum tolerated dose (MTD) or the highest protocol-defined dose in absence of exceeding the MTD, of the combination regimen of mogamulizumab and nivolumab subjects. Phase 1 will enroll up to 12 subjects. Phase 2 will explore the safety, efficacy and anti-tumor activity of the highest tolerated dose of the combination regimen. Phase 2 will enroll up to 184 subjects.

Inclusion criteria

• Subject is age 18 years or older;
• Subject must have histologically or cytologically confirmed solid tumor;
• Subject must have locally advanced or metastatic solid tumor;
• Subjects who have progressed or have been intolerant to any standard treatment regimen or refused standard treatment, or for which adequate standard therapy does not exist.
• Subjects who have evaluable lesion per guideline of Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
• Subject has an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1;
• If the subject is a woman of child-bearing potential or man who is sexually active with woman of child-bearing potential, the subject agrees to use adequate contraception from signing of the ICF, for the duration of study participation; and for 23 weeks after the last dose of IMP for women or 31 weeks after the last dose of IMP for men;
• Subjects who have adequate hematological, renal, hepatic and respiratory functions defined.
• The subject is willing to undergo tumor biopsy during the Screening period, or if the tumor is inaccessible for biopsy, archived tumor material must be available for submission;
• Subjects who voluntarily signed and dated Institutional Review Board approved informed consent form in accordance with regulatory and institutional guidelines.

Hepatocellular Carcinoma Inclusion Criteria:

• Histologically confirmed hepatocellular carcinoma not amenable for management with curative intent by surgery or local therapeutic measure;
• Subject must have received sorafenib treatment and either:

• have had documented radiographic or symptomatic progression during or after sorafenib therapy; OR
• be intolerant of sorafenib (defined as Grade 2 drug-related adverse event which 1) persisted in spite of comprehensive supportive therapy according to institutional standards AND 2) persisted or recurred after sorafenib treatment interruption of at least 7 days and dose reduction by one dose level (to 400 mg once daily) AND/OR Grade 3 drug-related adverse event which 1) persisted in spite of comprehensive supportive therapy according to institutional standards OR 2) persisted or recurred after sorafenib treatment interruption of at least 7 days and dose reduction by one dose level (to 400 mg once daily); OR must have documented refusal of sorafenib;
• Subject has Child-Pugh score of ≤6, i.e., Child-Pugh A (Appendix 2);
• INR ≤ 2.3 or Prothrombin time (PT) ≤ 6 seconds above control;
• Subject has HBV DNA viral load undetectable or < 100 IU/mL at screening. If subject has detectable HBsAg, HBeAg, or HBV DNA (indicating ongoing viral replication of hepatitis B, he/she must be on antiviral therapy per regional standard of care guidelines prior to initiation of study therapy. If not on antiviral therapy at screening, then the subject must initiate treatment per regional standard of care guidelines prior to C1D1 and must be willing to continue antiviral therapy while on study treatment.

Exclusion criteria

• Female subject who is pregnant or breast-feeding, or any subject expecting to conceive or father a child during this study;
• Subjects with uncontrolled and significant inter-current illness.
• Subjects has psychiatric illness/social situations that in the opinion of the investigator would limit compliance with study requirements;
• Subject has primary central nervous system (CNS) tumor or known CNS metastases and/or history of CNS metastases and/or carcinomatous meningitis; Exception: Subjects are eligible if CNS metastases are adequately treated and subjects are neurologically returned to baseline (except for residual signs or symptoms related to the CNS treatment) for at least 4 weeks prior to enrollment. In addition, subjects must be off corticosteroids for 4 weeks prior to enrollment.
• Subject has received prior therapy for cancer or major surgery within 28 days, or 42 days for nitrosourea or mitomycin C, prior to Cycle 1 Day 1, or 14 days for tamoxifen;
• Subject has received radiotherapy or radiosurgery within 14 days prior to Cycle 1 Day 1;
• Subject has been previously treated with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways;
• Subject has been previously treated with mogamulizumab;
• Subject has a history of allergy or hypersensitivity to study drug components;
• Subject has received a live, attenuated vaccine within 28 days prior to Cycle 1 Day 1;
• Subject has a history of organ transplant or allogeneic bone marrow transplant;
• Subject has any unresolved toxicity Grade > 1 from previous anti-cancer therapy
• Subject use of immunosuppressive medication within 14 days before Cycle 1 Day 1.
• Subjects who have known active autoimmune disease or a history of autoimmune disease which may affect vital organ function or require immune suppressive treatment including systemic corticosteroids;
• Subjects who have history of toxic epidermal necrolysis or Stevens-Johnson syndrome;
• Subjects who have a history of inflammatory bowel disease, Crohn's disease, ulcerative colitis, or Wegener's granulomatosis;
• Subject has primary or acquired immunodeficiency or known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome;
• Subject who tests positive for hepatitis B surface antigen (HBVsAg) or hepatitis C RNA indicating acute or chronic infection except for subjects with hepatocellular carcinoma;
• Subject has another active malignancy requiring concurrent intervention;
• Subject who is receiving any other investigational agents;
• Subject has another condition that, in the opinion of the Investigator and/or Sponsor, would interfere with evaluation of the IMP or interpretation of subject safety or study results;
• Subject has a history of pneumonitis or interstitial lung disease.

Hepatocellular Carcinoma Exclusion Criterion:

• Any history of hepatic encephalopathy
• Any prior (within 1 year) or current clinically significant ascites as measured by physical examination and that requires paracentesis for control;
• Active coinfection with both hepatitis B (i.e., HBVsAg and/or hepatitis B DNA) and hepatitis C (i.e., hepatitic C RNA)
• Hepatitis D infection in subjects with hepatitis B
• Any history of clinically meaningful variceal bleeding within the last three months.