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

Phase 1

Completed

Conditions: Hepatocellular Carcinoma
HCC
Solid Tumor
Cancer
Carcinoma

Interventions: Biological: Mogamulizumab + Nivolumab

Registration Number: NCT02705105

Lead Sponsor: Kyowa Kirin, Inc.

Brief Summary: The purpose of this study is to characterize the safety and tolerability and determine the maximum tolerated dose (MTD) or the recommended fixed dose of the combinations of mogamulizumab and nivolumab in subjects with locally advanced or metastatic solid tumors.

Detailed Description: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 114

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.

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Expansion Cohort	Mogamulizumab + Nivolumab	Cycle 1 Days 1, 8, 15, and 22: Maximum Tolerated Dose of Mogamulizumab + Nivolumab Subsequent Cycles Days 1 and 15: Maximum Tolerated Dose of Mogamulizumab + Nivolumab Subjects will be separated further into cohorts by tumor type
Dose-Finding Cohort	Mogamulizumab + Nivolumab	Cycle 1 Days 1, 8, 15, and 22: Dose Level 1 of Mogamulizumab + Nivolumab Subsequent Cycles Days 1 and 15: Dose Level 1 of Mogamulizumab + Nivolumab If \>1 patient has a DLT at first dose level, then the following cohort will be enrolled: Cycle 1 Days 1, 8, 15, and 22: Optional Dose Level of Mogamulizumab + Nivolumab Subsequent Cycles Days 1 and 15: Optional Dose Level of Mogamulizumab + Nivolumab

Primary Outcome Measures

Name	Time	Method
Maximum Tolerated Dose (MTD)	From the first dose of study medications until 14 days after the last dose of study medication	The MTD was defined as one dose level below the dose level of the cohort where ≥ one-third of the subjects experienced a dose-limiting toxicity (DLT)
Number of Subjects Experiencing Dose-limiting Toxicity	From the first dose of study medications until 14 days after the last dose of study medication	combination of mogamulizumab and nivolumab

Secondary Outcome Measures

Name	Time	Method
Objective Tumor Response Rate According to RECIST	From baseline to every 12 weeks, until data cut off	To evaluate the anti-tumor activity of the combination of mogamulizumab and nivolumab based on the Response Evaluation Criteria in Solid Tumors (RECIST) v. 1.1.