Trial of pIL-12/MK-3475 in Metastatic Melanoma

NCT02493361 | Completed Phase 2 Results DMC FDA Drug

• 2 other identifiers: 15852NCI-2015-01300
• Study Type: interventional
• Target: 24
• Locations: 1 country
• Sites: 2

Brief Summary

This is a multicenter, Phase II, open-label, 42-patient single-arm trial of intratumoral pIL-12 electroporation (EP) in combination with pembrolizumab in patients with melanoma. Patients will be evaluated in 2 parts. Part A patients will be selected using a flow cytometric assay that quantifies intratumoral PD-1hiCD8+CTLA4+ "exhausted" lymphocytes in the tumor. Part B will enroll patients who have or are failing pembrolizumab at least 12 weeks after starting Programmed cell death protein 1 (PD-1) antibody alone or in combination, or, who have been selected using a flow cytometric assay that quantifies intratumoral PD-1hiCD8+CTLA4+ "exhausted" lymphocytes in the tumor.

Conditions

Melanoma

Keywords

Pembrolizumab; Intratumoral pIL-12 Electroporation; Tumor-infiltrating lymphocyte melanoma

Outcome Measures

Primary Outcomes (1)

• Best Overall Objective Response Rate (ORR) Within 24 Weeks Using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1

  Best overall ORR within 24 weeks of first treatment with pIL-12 electroporation (EP) and pembrolizumab will be determined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by CT or MRI. The ORR is the proportion of participants with either a Complete Response (CR) defined as a disappearance of all target lesions determined by 2 separate scans conducted not \< 4 weeks apart and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm (the sum may not be "0" if there are target nodes) and no appearance of new lesions or a Partial Response (PR) defined as a \>=30% decrease in the sum of the longest diameter of target lesions with no appearance of new lesions. ORR = CR + PR.

  Up to week 24

Secondary Outcomes (6)

• Best Overall ORR Determined by Immune Related-Response Criteria (irRC)

  Up to 5 years

• Twenty-Four Week Landmark Progression Free Survival (PFS)

  At 24 weeks after treatment initiation

• Number of Participants With Treatment-related Adverse Events

  Up to 2 years

• Median PFS

  Up to 5 years

• Duration of Response (DOR) Estimate

  Up to 5 years

Study Arms (1)

Treatment

EXPERIMENTAL

Pembrolizumab: 200 mg IV, Day 1 of each cycle pIL-12: 1/4 tumor volume at concentration of 0.5 mg/mL intratumoral, Days 1, 5, and 8 of each odd cycle

Drug: Pembrolizumab; Drug: pIL-12

Interventions

Pembrolizumab DRUG

Treatment

pIL-12 DRUG

Treatment

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients must have histological or cytological diagnosis of melanoma with progressive locally advanced or metastatic disease that is not amenable to definitive local therapy with curative intent.
• At least one measurable tumor accessible for intratumoral injection and EP on investigator's assessment.
• Patients may have had prior chemotherapy or immunotherapy or radiation therapy. All prior therapies must be stopped 4 weeks prior to first dose of study treatment, with the exception of patients who have received ipilimumab, which must be stopped 6 weeks prior to first dose of study treatment. Patients are prohibited from receiving live vaccines within 30 days prior to first dose of study treatment.
• Age \>= 18 years
• Part A: Patient has agreed to two newly obtained tumor biopsies and as required re-biopsies (that can be biopsied on investigator's assessment) and to providing the acquired tissue for biomarker analysis. Analysis of one of the fresh biopsy samples for PD-1hiCD8+CTLA4hi in the CD8+CD45+ gate based on flow cytometry will be done. A second fresh biopsy sample is required for further biomarker analysis and confirmation at a later date of low PD-L1 expression using an Immunohistochemistry (IHC) assay for PD-L1 expression. A valid flow cytometry result is not required for study participation, but repeated biopsy for reanalysis is strongly recommended for patient with insufficient tumor-infiltrating lymphocytes (TIL) in the first tissue sample. Or:
• Part B: Anti-PD-1 non-responders are defined as those showing disease progression according to RECIST v1.1 after at least 12 weeks of therapy with a PD-1 antibody either alone or in combination with approved checkpoint inhibitor or targeted therapies according to their label. There is no serological requirement.
• Life expectancy of at least 6 months.
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1.
• Adequate organ function within 4 weeks of administration of study therapy:
• Lactate dehydrogenase (LDH): \<4 x upper limit of normal (ULN)
• Adequate hematological function:
• Absolute neutrophil count (ANC): \>=1,500/μL
• Platelets: \>=100,000/μL
• Hemoglobin: \>= 9 g/dL
• Adequate hepatic function:

You may not qualify if:

• Patient is currently participating or has participated in a study of an investigational agent or using an investigational device within 4 weeks of administration of study therapy.
• Patient is expected to require any other form of antineoplastic therapy while on study; including systemic chemotherapy, biological therapy, immunotherapy not specified in this protocol.
• Patient has uveal melanoma.
• Patient has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Patients with previously treated brain metastases may participate provided they are clinically stable without the use of systemic steroids for at least 8 weeks prior to study entry.
• Patient has risk factors for bowel obstruction or bowel perforation (examples include but not limited to a history of acute diverticulitis, intra-abdominal abscess, and abdominal carcinomatosis).
• Patient previously had a severe hypersensitivity reaction to treatment with another monoclonal antibody (mAb).
• Patient has a history of history of (non-infectious) pneumonitis or interstitial lung disease.
• Patient has active infection at time of study entry that require systemic antibiotics and/or with an oral temperature of \>= 38.3 degrees Celsius (°C)(100.9 degrees Fahrenheit (°F)) within 5 days of first treatment.
• Patients with electronic pacemakers or defibrillators are excluded from this study, as the effect of electroporation on these devices is unknown. Patients with lower extremity lesions may be discussed with the medical monitor.
• Patient has an active autoimmune disease or a documented history of autoimmune disease or syndrome that requires systemic steroids or immunosuppressive agents. Patients with vitiligo or resolved childhood asthma/atopy would be exception to this rule. Patients that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study. Patients with hypothyroidism that is stable on hormone replacement will not be excluded from the study.
• Patient has a medical condition that requires chronic systemic steroid therapy or requires any other form of immunosuppressive medication. However, patients using physiologic replacement doses of hydrocortisone, or its equivalent, will be considered eligible for this study; up to 20 mg hydrocortisone (or 5 mg of prednisone) in the morning and 10 mg hydrocortisone (or 2.5 mg of prednisone) in the evening.
• Pregnant women are excluded from this study because the potential for teratogenic or abortifacient effects upon treatment with pIL-12 EP + pembrolizumab is unknown. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with pIL-12 EP + pembrolizumab breastfeeding should be discontinued if the mother is treated with pIL-12 EP + pembrolizumab.
• Patients with symptomatic ascites or pleural effusion. A patient who is clinically stable following treatment for these conditions is eligible.
• Patient is Hepatitis C Virus (HCV) Ab positive or HBSAg positive.

Sponsors & Collaborators

• University of California, San Francisco: lead
• OncoSec Medical Incorporated: collaborator
• Merck Sharp & Dohme LLC: collaborator

Study Sites (2)

University of San Francisco, California

San Francisco, California, 94115, United States

Location

Huntsman Cancer Institute, University of Utah

Salt Lake City, Utah, 84112, United States

Location

Related Publications (1)

• Jacobs L, Yshii L, Junius S, Geukens N, Liston A, Hollevoet K, Declerck P. Intratumoral DNA-based delivery of checkpoint-inhibiting antibodies and interleukin 12 triggers T cell infiltration and anti-tumor response. Cancer Gene Ther. 2022 Jul;29(7):984-992. doi: 10.1038/s41417-021-00403-8. Epub 2021 Nov 9.

  PMID: 34754076 DERIVED

MeSH Terms

Conditions

Melanoma

Interventions

pembrolizumab

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases

Limitations and Caveats

Closed to enrollment earlier than expected due to high response rate in order to advance to phase 2b in proven PD1-refractory patients. A total of 24 patients were consented instead of the planned enrollment of 42 patients.

Results Point of Contact

• Title: Dr. Katy Tsai
• Organization: University of California, San Francisco

katy.tsai@ucsf.edu

(415) 402-5483

Study Officials

• Katy Tsai, MD

  University of California, San Francisco

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Clinical Assistant Professor

Study Record Dates

• First Submitted: July 6, 2015
• First Posted: July 9, 2015
• Study Start: August 17, 2015
• Primary Completion: April 26, 2018
• Study Completion: March 2, 2020
• Last Updated: January 6, 2021
• Results First Posted: August 21, 2019

Record last verified: 2020-12

Data Sharing

• IPD Sharing: Will not share

Locations

US (2)