Cancer, Carcinoma, HCC, Hepatocellular Carcinoma, Solid Tumor
Conditions
Keywords
Metastatic Solid Tumors, Advanced Solid Tumors, KW-0761, ONO-4538/BMS-936558, Anti-tumor, Mogamulizumab, Nivolumab, Oncology, HCC, Hepatocellular carcinoma
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.
Interventions
BIOLOGICALMogamulizumab + Nivolumab
i.v. administration
Sponsors
Bristol-Myers Squibb
Kyowa Kirin, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| All in Phase 1 Cohort All subjects in dose-finding cohort | 4 |
| NSCLC, Squamous Cell Subjects in expansion cohort with squamous cell NSCLC | 5 |
| NSCLC, Nonsquamous, PD-L1 Non-Expressing Subjects in expansion cohort with non-expressing, nonsquamous, PD-L1 NSCLC | 4 |
| Squamous Cell Carcinoma of Head and Neck Subjects in expansion cohort with head & neck squamous cell carcinoma | 10 |
| Colorectal Carcinoma, Non-MSI High Subjects in expansion cohort with colorectal carcinoma | 29 |
| Ovarian/Fallopian Tube/Primary Peritoneal Carcinoma Subjects in expansion cohort with ovarian cancer, primary peritoneal cancer, or fallopian tube carcinoma | 21 |
| Hepatocellular Carcinoma (HCC) Subjects in expansion cohort with hepatocellular carcinoma | 24 |
| Pancreatic Adenocarcinoma Subjects in expansion cohort with pancreatic adenocarcinoma | 17 |
| Total | 114 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Follow-Up | Death | 3 | 68 |
| Follow-Up | Discontinued per Amendment 3 | 0 | 2 |
| Follow-Up | Study Terminated | 0 | 26 |
| Follow-Up | Withdrawal by Subject | 1 | 14 |
| Treatment | Adverse Event | 0 | 17 |
| Treatment | Clinical Disease Progression | 0 | 32 |
| Treatment | Objective Disease Progression | 1 | 50 |
| Treatment | Ongoing w/ Treatment at time of data cut | 0 | 2 |
| Treatment | Physician Decision | 0 | 3 |
| Treatment | Withdrawal by Subject | 3 | 5 |
Baseline characteristics
| Characteristic | NSCLC, Squamous Cell | NSCLC, Nonsquamous, PD-L1 Non-Expressing | Squamous Cell Carcinoma of Head and Neck | Colorectal Carcinoma, Non-MSI High | Ovarian/Fallopian Tube/Primary Peritoneal Carcinoma | Hepatocellular Carcinoma (HCC) | All in Phase 1 Cohort | Pancreatic Adenocarcinoma | Total |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 4 Participants | 2 Participants | 4 Participants | 4 Participants | 7 Participants | 14 Participants | 2 Participants | 12 Participants | 49 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants | 2 Participants | 6 Participants | 25 Participants | 14 Participants | 10 Participants | 2 Participants | 5 Participants | 65 Participants |
| Age, Continuous | 68.8 years | 65.5 years | 60.2 years | 53.8 years | 61.2 years | 65.4 years | 58.3 years | 67.1 years | 61.4 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 1 Participants | 2 Participants | 1 Participants | 1 Participants | 0 Participants | 1 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants | 4 Participants | 7 Participants | 25 Participants | 18 Participants | 21 Participants | 4 Participants | 16 Participants | 99 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 2 Participants | 2 Participants | 2 Participants | 2 Participants | 0 Participants | 0 Participants | 9 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 0 Participants | 4 Participants | 3 Participants | 3 Participants | 1 Participants | 0 Participants | 13 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 4 Participants | 3 Participants | 10 Participants | 24 Participants | 17 Participants | 20 Participants | 3 Participants | 16 Participants | 97 Participants |
| Region of Enrollment United States | 5 Participants | 4 Participants | 10 Participants | 29 Participants | 21 Participants | 24 Participants | 4 Participants | 17 Participants | 114 Participants |
| Sex: Female, Male Female | 3 Participants | 2 Participants | 2 Participants | 11 Participants | 21 Participants | 1 Participants | 2 Participants | 11 Participants | 53 Participants |
| Sex: Female, Male Male | 2 Participants | 2 Participants | 8 Participants | 18 Participants | 0 Participants | 23 Participants | 2 Participants | 6 Participants | 61 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 4 | 0 / 5 | 0 / 4 | 0 / 10 | 1 / 29 | 0 / 21 | 2 / 24 | 3 / 17 |
| other Total, other adverse events | 4 / 4 | 5 / 5 | 4 / 4 | 10 / 10 | 28 / 29 | 21 / 21 | 24 / 24 | 17 / 17 |
| serious Total, serious adverse events | 2 / 4 | 2 / 5 | 3 / 4 | 6 / 10 | 18 / 29 | 11 / 21 | 17 / 24 | 11 / 17 |
Outcome results
Primary
Maximum Tolerated Dose (MTD)
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)
Time frame: From the first dose of study medications until 14 days after the last dose of study medication
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| All in Phase 1 Cohort | Maximum Tolerated Dose (MTD) | Subjects enrolled at Dose Level 1 | 4 Participants |
| All in Phase 1 Cohort | Maximum Tolerated Dose (MTD) | Subjects who successfully tolerated Dose Level 1 | 4 Participants |
Primary
Number of Subjects Experiencing Dose-limiting Toxicity
combination of mogamulizumab and nivolumab
Time frame: From the first dose of study medications until 14 days after the last dose of study medication
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| All in Phase 1 Cohort | Number of Subjects Experiencing Dose-limiting Toxicity | Subjects enrolled at Dose Level 1 | 4 Participants |
| All in Phase 1 Cohort | Number of Subjects Experiencing Dose-limiting Toxicity | Subjects who experienced DLT at Dose Level 1 | 0 Participants |
Secondary
Objective Tumor Response Rate According to RECIST
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.
Time frame: From baseline to every 12 weeks, until data cut off
Population: Efficacy Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All in Phase 1 Cohort | Objective Tumor Response Rate According to RECIST | 25 percentage of participants |
| NSCLC, Squamous Cell | Objective Tumor Response Rate According to RECIST | 20 percentage of participants |
| NSCLC, Nonsquamous, PD-L1 Non-expressing | Objective Tumor Response Rate According to RECIST | 25 percentage of participants |
| Squamous Cell Carcinoma of Head and Neck | Objective Tumor Response Rate According to RECIST | 10 percentage of participants |
| Colorectal Carcinoma, Non-MSI Hign | Objective Tumor Response Rate According to RECIST | 3.4 percentage of participants |
| Ovarian/Fallopian Tube/Primary Peritoneal Carcinoma | Objective Tumor Response Rate According to RECIST | 14.3 percentage of participants |
| Hepatocellular Carcinoma | Objective Tumor Response Rate According to RECIST | 16.7 percentage of participants |
| Pancreatic Adenocarcinoma | Objective Tumor Response Rate According to RECIST | 0 percentage of participants |