Talimogene Laherparepvec and Panitumumab for the Treatment of Locally Advanced or Metastatic Squamous Cell Carcinoma of the Skin

• ClinicalTrials.gov Identifier: NCT04163952
• Recruitment Status: Active, not recruiting
• First Posted: November 15, 2019
• Last Update Posted: May 13, 2022
• Sponsor: Rutgers, The State University of New Jersey
• Collaborator: National Cancer Institute (NCI)
• Information provided by (Responsible Party): Adam Berger, MD, Rutgers Cancer Institute of New Jersey

Study Description

Brief Summary:

This phase I trial studies the side effects and how well talimogene laherparepvec and panitumumab work in treating patients with squamous cell carcinoma of the skin that has spread to nearby tissues or lymph nodes (locally advanced) or other places in the body (metastatic). Talimogene laherparepvec is a type of vaccine made from a gene-modified virus that may help the body build an effective immune response to kill tumor cells. Immunotherapy with monoclonal antibodies, such as panitumumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving talimogene laherparepvec and panitumumab may work better in treating patients with squamous cell carcinoma of the skin compared to panitumumab alone.

Condition or disease	Intervention/treatment	Phase
Locally Advanced Skin Squamous Cell Carcinoma; Metastatic Skin Squamous Cell Carcinoma; Recurrent Skin Squamous Cell Carcinoma	Biological: Panitumumab; Biological: Talimogene Laherparepvec	Phase 1

Detailed Description:

PRIMARY OBJECTIVES:

I. To determine the safety of the combined treatment of talimogene laherparepvec and panitumumab.

II. To determine the preliminary efficacy of the combined treatment of talimogene laherparepvec and panitumumab, in comparison to single-agent panitumumab by historical control.

SECONDARY OBJECTIVES:

I. To assess the clinical efficacy of panitumumab in combination with intratumoral talimogene laherparepvec in terms of immune-related progression-free survival (irPFS) at 12 months, progression-free survival (PFS) hazard ratio, overall response rate (ORR), 1-year survival, overall survival (OS) and time to resectability.

II. To measure the pathologic complete response rate to panitumumab combined with talimogene laherparepvec.

III. Assess the response of injected and non-injected tumor deposits after panitumumab and talimogene laherparepvec.

IV. Assess the time to initial response. V. Assess the durable response rate.

VI. To analyze the following molecular correlates with response to therapy to confirm mechanism of action, and identify potential future targeted strategies and biomarkers of response:

VIa. Mutation load in tumor tissue by next generation sequencing. VIb. Deoxyribonucleic acid (DNA) mutation signature in tumor tissue pre- and post-therapy by next generation sequencing.

VIc. Messenger ribonucleic acid (mRNA) signature in tumor tissue pre-and post-therapy by Nanostring technology.

VId. Immune cell populations and immune profile in pre- and post-therapy tumor tissue and peripheral blood by flow cytometry and immunohistochemistry (IHC).

OUTLINE:

Patients receive talimogene laherparepvec intratumorally (IM) on day 1. Patients then receive talimogene laherparepvec IM and panitumumab intravenously (IV) over 30-90 minutes on day 22. Treatment repeats every 2 weeks for up to 3 cycles in the absence of disease progression or unacceptable toxicity. Patients may receive up to 3 additional cycles of treatment per physician discretion.

After completion of study treatment, patients are followed up at 30 days and then every 2 months for 2 years.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 5 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 1 Study of Talimogene Laherparepvec and Panitumumab in Patients With Locally Advanced Squamous Cell Carcinoma of the Skin (SCCS)
• Actual Study Start Date: January 31, 2020
• Estimated Primary Completion Date: September 30, 2024
• Estimated Study Completion Date: September 30, 2024

Arms and Interventions

Arm

Intervention/treatment

Experimental: Treatment (talimogene laherparepvec, panitumumab); Patients receive talimogene laherparepvec IM on day 1. Patients then receive talimogene laherparepvec IM and panitumumab IV over 30-90 minutes on day 22. Treatment repeats every 2 weeks for up to 3 cycles in the absence of disease progression or unacceptable toxicity. Patients may receive up to 3 additional cycles of treatment per physician discretion.

Biological: Panitumumab; Given IV; Other Names: ABX-EGF; ABX-EGF Monoclonal Antibody; ABX-EGF, Clone E7.6.3; MoAb ABX-EGF; Monoclonal Antibody ABX-EGF; Vectibix; Biological: Talimogene Laherparepvec; Given IM; Other Names: ICP34.5-, ICP47-deleted Herpes Simplex Virus 1 (HSV-1) Incorporating the Human GM-CSF Gene; Imlygic; JS1 34.5-hGMCSF 47- pA-; T-VEC

Outcome Measures

Primary Outcome Measures :

1. Incidence of adverse events [ Time Frame: Up to 30 days ]
   Will be based on National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0.
2. Response rate to panitumumab and talimogene laherparepvec [ Time Frame: Up to 2 years ]
   Will be assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.

Secondary Outcome Measures :

1. Best overall response rate (ORR) [ Time Frame: Up to 2 years ]
   Will be defined as the best response as recorded from the start of study drug until disease progression. ORR is defined as the proportion of patients with a best ORR characterized as either a complete response or partial response relative to the total number of evaluable patients. The response rate of the drug will be assessed according to the decision rule based on Simon?s two-stage design.
2. Durable response rate [ Time Frame: Up to 2 years ]
   Will be defined as the percent of patients with complete response or partial response maintained continuously for a minimum of 6 months. The response rate of the drug will be assessed according to the decision rule based on Simon?s two-stage design.
3. Duration of response [ Time Frame: Time from initial response until document progression, assessed up to 2 years ]
   The response rate of the drug will be assessed according to the decision rule based on Simon?s two-stage design.
4. Progression-free survival (PFS) [ Time Frame: From date of enrollment to the date of death or progression, whichever occurred earlier (per RECIST 1.1), assessed up to 2 years ]
   The estimate of PFS will be performed by the Kaplan-Meier product limit model. Logrank test and Cox proportional hazards model will be used to explore the associations between PFS and patient characteristics.
5. Overall survival (OS) [ Time Frame: From date of enrollment to the date of death or date last known alive, assessed up to 2 years ]
   The estimate of OS will be performed by the Kaplan-Meier product limit model. Logrank test and Cox proportional hazards model will be used to explore the associations between OS and patient characteristics.
6. Mutation load in tumor tissue [ Time Frame: Up to 2 years ]
   Will be analyzed by next generation sequencing with response to therapy. Molecular correlates will also be obtained and descriptive statistics applied.
7. Deoxyribonucleic acid mutation signature in tumor tissue [ Time Frame: Up to 2 years ]
   Will be analyzed by next generation sequencing with response to therapy. Molecular correlates will also be obtained and descriptive statistics applied.
8. Messenger ribonucleic acid signature in tumor tissue [ Time Frame: Up to 2 years ]
   Will be analyzed by Nanostring technology with response to therapy. Molecular correlates will also be obtained and descriptive statistics applied.
9. Immune cell populations in tumor tissue [ Time Frame: Up to 2 years ]
   Will be analyzed by flow cytometry and immunohistochemistry with response to therapy. Molecular correlates will also be obtained and descriptive statistics applied.
10. Immune cell populations peripheral blood [ Time Frame: Up to 2 years ]
    Will be analyzed by flow cytometry and immunohistochemistry with response to therapy. Molecular correlates will also be obtained and descriptive statistics applied.
11. Expression of Cytokines in tumor tissue [ Time Frame: Up to 2 years ]
    Will be analyzed by flow cytometry and immunohistochemistry with response to therapy. Molecular correlates will also be obtained and descriptive statistics applied.
12. Expression of Cytokines in peripheral blood [ Time Frame: Up to 2 years ]
    Will be analyzed by flow cytometry and immunohistochemistry with response to therapy. Molecular correlates will also be obtained and descriptive statistics applied.
13. Pathologic complete response rate [ Time Frame: Up to 2 years ]
14. Time to resectability [ Time Frame: Up to 2 years ]

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:

• Histologically confirmed squamous cell carcinoma of the skin (SCCS) that is a) locally advanced or metastatic for which curative surgery or radiation would be difficult or impossible, or b) recurrent after initial surgery, chemotherapy, or radiation therapy, or c) considered to have aggressive features including the following: tumors 2 cm or more, tumors invading deep tissues such as muscle, cartilage or bone; tumors showing perineural invasion, and/or tumors metastatic to loco-regional lymph nodes. Patients may have had prior surgical interventions or been treated with investigational agents with residual or recurrent disease
• Tumor suitable for direct or ultrasound-guided injection defined as at least one cutaneous, subcutaneous, or nodal lesion, or aggregate of lesions, >= 10 mm in diameter
• Eastern Cooperative Oncology Group (ECOG) performance status =< 2
• No prior treatment with panitumumab or talimogene laherparepvec for advanced disease
• Prior surgery or radiation is allowed if there is documented progression in the radiated/resected area or elsewhere by Response Evaluation Criteria in Solid Tumors (RECIST) criteria version (v) 1.1
• Measurable disease by RECIST criteria v 1.1
• Patients with a history of hematologic or solid organ transplant will be considered if they do not require high dose steroids or high dose immunosupressants for disease control or control of transplant rejection, and have adequate hematologic, renal, and hepatic function as specified below. Current medications must be reviewed with transplant pharmacy team to exclude potentially serious interactions and case discussed with the study principal investigator (PI)
• Second primary malignancy only if treatment would interfere with the patient?s participation in this trial in the opinion of the treating physician. Clear exceptions are 1) patient had a second primary malignancy but has been treated and disease free for at least 3 years, 2) in situ carcinoma (e.g., in situ carcinoma of the cervix) and, 3) additional skin cancers that have been definitively treated by surgery and/or radiation. Patients with chronic lymphocytic leukemia will be allowed if their blood counts are within acceptable hematologic parameters and if they are not currently requiring cytotoxic or biologic anticancer treatment (supportive treatment such as intravenous immunoglobulin [IVIG] is permitted)
• Patients with autoimmune disorders will be considered if they do not require high dose steroids or other immunosuppressants for disease control. Prednisone in daily doses up to 10 mg and inhaled steroids are acceptable
• Absolute neutrophil count (ANC) >= 1500/uL
• Platelet count >= 100,000/mm^2
• Hemoglobin >= 9 g/dL
• Total bilirubin < 1.5 x institutional upper limit of normal (ULN); if patient has conditions of congenital hyperbilirubinemia, then patient must have isolated hyperbilirubinemia (e.g., no other liver function test abnormalities) with maximum bilirubin < 2 x institutional ULN
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) =< 2.5 x institutional ULN in absence of liver metastases; =< 5 x ULN in presence of liver metastases
• Alkaline phosphatase < 2.5 x institutional ULN
• Creatinine < 1.5 x institutional ULN or calculated creatinine clearance >= 60 mL/min as estimated using the Cockcroft-Gault formula

Exclusion Criteria:

• Pregnant women. Women of childbearing age must be willing to undergo a pregnancy test prior to therapy and to use adequate contraception (e.g., hormonal or barrier method of contraception or abstinence) for the duration of the study and 6 months thereafter. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. Menopausal status will be defined as one or more of successful hysterectomy, bilateral tubal ligation or bilateral oophorectomy, amenorrhea >= 12 consecutive months without another cause, or a documented serum follicle stimulating hormone (FSH) >= 35 mIU/mL
• Tumor not suitable for direct or ultrasound-guided injection
• Prior treatment with talimogene laherparepvec for advanced disease
• Patients with active, uncontrolled infections including active herpetic infections or chronic herpetic infections requiring anti-viral therapy (e.g., acyclovir)
• Patients without adequate organ function as documented above
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to panitumumab, talimogene laherparepvec or other agents used in the study
• History of interstitial pneumonitis, pulmonary fibrosis, or evidence of interstitial pneumonitis

Contacts and Locations

Locations

United States, New Jersey

Rutgers Cancer Institute of New Jersey

New Brunswick, New Jersey, United States, 08903

United States, North Carolina

Duke University Medical Center - Duke Cancer Center

Durham, North Carolina, United States, 27710

Sponsors and Collaborators

Rutgers, The State University of New Jersey

National Cancer Institute (NCI)

Investigators

• Principal Investigator: Adam C Berger, MD, FACS; Rutgers Cancer Institute of New Jersey

More Information

• Responsible Party: Adam Berger, MD, Associate Director for Shared Resources, Chief of Melanoma and Soft Tissue Sarcoma Surgical Oncology, Rutgers Cancer Institute of New Jersey
• ClinicalTrials.gov Identifier: NCT04163952
• Other Study ID Numbers: Pro2018002628; NCI-2019-06083 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); Pro2018002628; 091804 ( Other Identifier: Rutgers Cancer Institute of New Jersey ); P30CA072720 ( U.S. NIH Grant/Contract )
• First Posted: November 15, 2019
• Last Update Posted: May 13, 2022
• Last Verified: May 2022

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

Additional relevant MeSH terms:

Carcinoma; Carcinoma, Squamous Cell; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Squamous Cell; Antineoplastic Agents, Immunological; Panitumumab; Talimogene laherparepvec; Antibodies; Immunoglobulins; Antibodies, Monoclonal; Immunologic Factors; Physiological Effects of Drugs; Antineoplastic Agents