A Study of Combination Treatment With HF10 and Ipilimumab in Patients With Unresectable or Metastatic Melanoma

• ClinicalTrials.gov Identifier: NCT02272855
• Recruitment Status: Completed
• First Posted: October 23, 2014
• Last Update Posted: September 26, 2018
• Sponsor: Takara Bio Inc.
• Collaborator: Theradex
• Information provided by (Responsible Party): Takara Bio Inc.

Study Description

Brief Summary:

The purpose of this study is to determine if HF10 in combination with ipilimumab is effective in patients with stages IIIB, IIIC, or IV unresectable or metastatic melanoma.

Condition or disease	Intervention/treatment	Phase
Malignant Melanoma	Biological: HF10 plus Ipilimumab	Phase 2

Detailed Description:

The study is designed to assess efficacy and safety with repeated administration of intratumoral injections of HF10 at 1x10^7 TCID50/mL in combination with intravenous infusions of 3mg/kg ipilimumab. This is a single arm, open label Phase II trial, to evaluate the efficacy, safety and tolerability of HF10 treatment in combination with administration of the immunologic checkpoint inhibitor, ipilimumab (anti-CTLA-4 monoclonal antibody). The study population will include patients with Stage IIIB, IIIC or IV unresectable or metastatic malignant melanoma who are ipilimumab-eligible.

Patients will receive the dose of 1 x 10^7 TCID50/mL HF10 (for a total of 6 injections; the first 4 injections at 1-week intervals; the remaining 2 injections at 3-week intervals) + ipilimumab at 3 mg/kg ipilimumab (for a total of 4 intravenous infusions, each administered at 3-week intervals).

Following combination therapy, patients may continue to receive the same dose level of HF10 (1 x 10^7 TCID50/mL) alone for up to an additional 13 injections (total of 19 injections = 1 year) if they have tolerated the study treatment, are responding, have stable disease, or have progressive disease that is not clinically significant in the judgment of the Investigator.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 46 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Study of Combination Treatment With HF10, a Replication-competent HSV-1 Oncolytic Virus, and Ipilimumab in Patients With Stage IIIB, Stage IIIC, or Stage IV Unresectable or Metastatic Malignant Melanoma
• Actual Study Start Date: April 30, 2014
• Actual Primary Completion Date: October 2016
• Actual Study Completion Date: August 2018

Arms and Interventions

Arm	Intervention/treatment
Experimental: HF10 plus ipilimumab	Biological: HF10 plus Ipilimumab; Patients will receive the dose of 1 x 10^7 TCID50/mL HF10 (for a total of 6 injections; the first 4 injections at 1-week intervals; the remaining 2 injections at 3-week intervals) and ipilimumab at 3 mg/kg ipilimumab (for a total of 4 intravenous infusions, each administered at 3-week intervals).; Other Name: YERVOY (for ipilimumab)

Outcome Measures

Primary Outcome Measures :

1. Best overall response rate (BORR) [ Time Frame: at 24 weeks ]

Secondary Outcome Measures :

1. Adverse Event Summaries, Vital Signs, and Laboratory Parameters as a Measure of Safety and Tolerability [ Time Frame: until Week 24 ]
   Adverse events will be evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE version 4.0).
2. Objective response rate (ORR) [ Time Frame: at Weeks 12, 18, and 24 ]
3. Progression-free survival (PFS) [ Time Frame: for 1 year ]
4. Durable response rate (DRR) [ Time Frame: for 1 year ]
5. 1-year survival rate [ Time Frame: at 1 year ]
6. Accumulation of Lymphocytes in the Tumor by using Core Biopsy Samples [ Time Frame: pre-treatment screening and Week 24 ]
7. Change in Cytokine Profiles by using Peripheral Blood Samples [ Time Frame: pre-treatment screening and Week 24 ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Patients must have Stage IIIB, IIIC or IV melanoma, which is unresectable/unresected or histologically confirmed diagnosis of metastatic malignant melanoma.
2. Patients must have measurable non-visceral lesion(s) that are evaluable by the modified World Health Organization (mWHO) criteria and immune-related response criteria (irRC).
3. Patients must be ≥ 18 years of age.
4. Patients must have a life expectancy ≥ 24 weeks.
5. Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.

6. Patients must have adequate hepatic function, defined as

   • Total bilirubin levels ≤ 1.5 x upper limit of normal [ULN] (except for patients with Gilbert's Syndrome, who must have a total bilirubin of less than 3.0 mg/dL)
   • AST/ALT levels ≤ 2.5 x ULN, or ≤ 5 x ULN if liver metastases are present.
7. Patients must have adequate renal function, defined as serum creatinine ≤ 1.5 x ULN or creatinine clearance (calculated) ≥ 60 mL/min/1.73 m2 for patients with creatinine > 1.5 x ULN.

8. Patients must have adequate bone marrow function, defined as

   • Absolute neutrophil count ≥1,500/µL and
   • Platelet count ≥ 75,000/ µL
9. Patients must have no known bleeding diathesis or coagulopathy that would make intratumoral injection or biopsy unsafe.
10. Patients must be ipilimumab-eligible. (This includes: 1) patients previously untreated with ipilimumab; 2) patients previously treated (more than 1 year previously) with ipilimumab using a route of administration other than intravenous infusion; and 3) patients previously treated with antitumor agents other than intravenous ipilimumab).
11. Men and women of childbearing potential must agree to use adequate contraception from the time of consent through 30 days after final study treatment.
12. Females of childbearing potential must have a negative urine or serum pregnancy test within one week prior to start of treatment.
13. Patients must be able to understand and willing to sign a written informed consent document.

Exclusion Criteria:

1. Patients receiving chemotherapy or radiotherapy within 4 weeks of injection of HF10, or history of Grade 4 adverse events or presence of adverse events Grade 2 or greater, except alopecia, resulting from anticancer agents administered more than 4 weeks prior to HF10 injection.
2. Patients receiving anti-herpes medication within 1 week prior to initiating HF10 treatment.
3. Patients with a history of significant tumor bleeding, or coagulation or bleeding disorders.
4. Patients with target tumors that could potentially invade a major vascular structure (e.g., innominate artery, carotid artery), based on unequivocal imaging findings.
5. Patients with Grade 2 or greater pre-existing neurologic abnormalities (CTCAE version 4.0), including Grade 2 or greater peripheral neuropathy caused by previous treatments.
6. Patients with clinically evident Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), Hepatitis C virus (HCV), or Epstein-Barr virus (EBV) infection are excluded.
7. Medical history of autoimmune disease (e.g., Crohn's disease, ulcerative colitis) or other diseases requiring systemic glucocorticoid or immunosuppressive therapy.
8. Patients who were previously treated with ipilimumab administered by intravenous infusion.
9. Concurrent use of any other investigational agents.
10. Patients with active CNS metastases or carcinomatous meningitis, except patients with CNS lesions that have been treated and have no evidence of progression in the brain on CT/MRI for ≥ 3 months.
11. Pregnant or breastfeeding women; women desiring to become pregnant within the timeframe of the study are also excluded.
12. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements, as determined by the investigator.

Contacts and Locations

Locations

United States, California

Clinical Site

San Francisco, California, United States, 94115

United States, Georgia

Clinical Site

Atlanta, Georgia, United States, 30322

United States, Oregon

Clinical Site

Portland, Oregon, United States, 97239

United States, Pennsylvania

Clinical Site

Bethlehem, Pennsylvania, United States, 18015

Clinical Site

Hershey, Pennsylvania, United States, 17033

United States, Texas

Clinical Site

Dallas, Texas, United States, 75230

Clinical Site

Houston, Texas, United States, 77030

United States, Utah

Clinical Site

Salt Lake City, Utah, United States, 84112

Sponsors and Collaborators

Takara Bio Inc.

Theradex

Investigators

• Principal Investigator: Robert Andtbacka; University of Utah

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Watanabe D, Goshima F. Oncolytic Virotherapy by HSV. Adv Exp Med Biol. 2018;1045:63-84. doi: 10.1007/978-981-10-7230-7_4. Review.

• Responsible Party: Takara Bio Inc.
• ClinicalTrials.gov Identifier: NCT02272855
• Other Study ID Numbers: T14-10682
• First Posted: October 23, 2014
• Last Update Posted: September 26, 2018
• Last Verified: September 2018

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Takara Bio Inc.:

HF10; HSV-1; Ipilimumab; Oncolytic virus; Phase II; Stage IIIB melanoma; Stage IIIC melanoma; Stage IV melanoma; Unresectable malignant melanoma; Metastatic malignant melanoma; Combination treatment; Intratumoral injection

Additional relevant MeSH terms:

Melanoma; Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Ipilimumab; Antineoplastic Agents, Immunological; Antineoplastic Agents