Combining Talimogene Laherparepvec With BRAF and MEK Inhibitors in BRAF Mutated Advanced Melanoma

• ClinicalTrials.gov Identifier: NCT03088176
• Recruitment Status: Recruiting
• First Posted: March 23, 2017
• Last Update Posted: October 1, 2019
• Sponsor: West Cancer Center
• Collaborators: University of Tennessee Health Science Center; Amgen
• Information provided by (Responsible Party): West Cancer Center

Study Description

Brief Summary:

The purpose of the study is to determine safety and tolerability of the combination of talimogene laherparepvec in combination with dabrafenib and trametinib in BRAF mutated advanced melanoma.

Condition or disease	Intervention/treatment	Phase
Melanoma; BRAF Gene Mutation	Drug: Talimogene Laherparepvec 1 Million Pfu/Ml Inj,Susp,1Ml,Vil; Drug: Talimogene Laherparep 100 Mil Pfu/Ml 1Ml; Drug: Dabrafenib; Drug: Trametinib	Phase 1

Detailed Description:

While targeted therapies can successfully block oncogenic signaling in BRAF mutant melanoma, activation of an immune response with agents such as talimogene laherparepvec can induce durable responses in a subset of patients. Combining BRAF inhibitors and immunotherapy may specifically target the BRAF driver mutation in the tumor cells and potentially sensitize the immune system to target tumors.

The study will enroll up to 20 patients with advanced melanoma and activating mutations in the BRAF gene for the local administration of talimogene laherparepvec in conjunction with oral therapy with dabrafenib and trametinib, to describe the safety and tolerability of this combination.

Talimogene laherparepvec will be administered by intralesional injection into injectable cutaneous, subcutaneous, or nodal lesions with or without image ultrasound guidance. Talimogene laherparepvec will not be administered into any visceral organ or mucosal membrane lesions. The initial dose of talimogene laherparepvec is up to 4.0 mL of 106 plaque forming units (PFU)/mL. Subsequent doses of talimogene laherparepvec are up to 4.0 mL of 108 PFU/mL. The second dose of talimogene laherparepvec (the first dose of the 108 PFU formulation), will be administered at least 21 days following the initial dose. Subsequent doses will be given approximately every 2 weeks.

Dabrafenib at a dose of 150mg will be self-administered orally twice per day. Trametinib at a dose 2mg will be self-administered orally once per day.

Subjects will be evaluated by physical exam at the beginning of Cycle 1 (Week 1), Cycle 2 (Week 4), Cycle 3 (Week 6), Cycle 4 (Week 8), and every two cycles thereafter. Subjects will be evaluated for dose-limiting toxicities (defined in protocol) at Cycle 2 (Week 4), Cycle 3 (Week 6), and Cycle 4 (Week 8). Efficacy evaluation will be performed by tumor measurements using clinical assessment, CT or PET/CT every 4 cycles with the first non-baseline measurement prior to Cycle 4. Tumor response will be evaluated using RECIST 1.1. Adverse events will be recorded and graded using the Common Terminology Criteria for Adverse Events Version 4.0 (CTCAE v4.0). Other safety assessments will include clinical laboratory values and physical exam findings. Reporting of adverse events, serious adverse events, and documentation of concomitant medications will occur as needed and at every cycle. Biopsy of a melanoma lesion (preferably uninjected) should occur at least one day prior to Cycle 4 (Week 8). Blood for biomarker analysis will be obtained immediately prior to the on-treatment biopsy, or if the on-treatment biopsy cannot be performed, immediately prior to Cycle 4 (Week 8).

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 20 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Intervention Model Description: Phase 1b single arm single dose level
• Masking: None (Open Label)
• Masking Description: No masking
• Primary Purpose: Treatment
• Official Title: A Phase 1b Trial of Talimogene Laherparepvec in Combination With Dabrafenib and Trametinib in Advanced Melanoma With an Activating BRAF Mutation
• Actual Study Start Date: June 25, 2017
• Estimated Primary Completion Date: June 30, 2020
• Estimated Study Completion Date: June 30, 2021

Arms and Interventions

Arm	Intervention/treatment
Experimental: Combination; Talimogene laherperepvec intratumoral injection up to 4ml of 10^6 PFU/mL on Day 1, followed by up to 4mL of 10^8 PFU/mL 3 weeks later, followed by every 2 weeks thereafter for up to two years. Dabrafenib 150mg orally twice daily for up to two years Trametinib 2mg orally once daily for up to two years	Drug: Talimogene Laherparepvec 1 Million Pfu/Ml Inj,Susp,1Ml,Vil; Up to 4mL administered on C1D1 intratumorally; Other Name: Imlygic; Drug: Talimogene Laherparep 100 Mil Pfu/Ml 1Ml; Up to 4 ML administered on Week 4 Day 1 and every 2 weeks thereafter; Other Name: Imlygic; Drug: Dabrafenib; 150mg PO qday; Other Name: Tafinlar; Drug: Trametinib; 2mg PO qday; Other Name: Mekinist

Outcome Measures

Primary Outcome Measures :

1. Rate of Dose Limiting Toxicities (DLT) [ Time Frame: 2 years ]
   Number of DLT seen in the subject population

Secondary Outcome Measures :

1. Progression Free Survival [ Time Frame: 4 years ]
   per RECIST 1.1
2. Objective Response Rate [ Time Frame: 4 years ]
   per RECIST 1.1
3. Change in tumor burden [ Time Frame: 4 years ]
   Best change in tumor diameters
4. Time to Response [ Time Frame: 4 years ]
   In responding patients, time from first dose to achieving objective response
5. Duration of Response [ Time Frame: 4 years ]
   In responding patients, time from first evidence of objective response until progression or end of study

Other Outcome Measures:

1. Lesion-level objective response [ Time Frame: 4 years ]
   Change in diameters of individual lesions
2. Biomarker analysis [ Time Frame: 4 years ]
   Exploratory analysis including number of participants with changes in CD8+ tumor infiltrating lymphocytes between pre-study and on-study biopsies

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. Age ≥ 18
2. Primary or recurrent Stage IIIB to IVM1c melanoma for whom surgery is not recommended
3. Activating BRAF mutation (limited to V600E or V600K mutations if being treated first-line, but can include any well-defined BRAF mutation after failure of prior immunotherapy)

4. Measurable disease defined as follows: At least one melanoma lesion that can be accurately and serially measured in one dimension and for which the longest diameter is ≥10 mm as measured by calipers, CT scan, or MRI.

   a. If all lesions are lymph nodes, at least one node must be able to be accurately and serially measured in two dimensions, and the short-axis must be ≥15mm.

5. Injectable disease (defined as at least 1cm of disease in areas suitable for injection including cutaneous, subcutaneous, or nodal lesions)

Exclusion Criteria:

1. Prior therapy with talimogene laherparepvec
2. Prior therapy with the combination of dabrafenib and trametinib

3. Evidence of clinically significant immunosuppression such as the following:

   1. Primary immunodeficiency state such as Severe Combined Immunodeficiency Disease
   2. Concurrent opportunistic infection
   3. Receiving chronic systemic immunosuppressive therapy (> 2 weeks), including oral steroid doses > 10mg/day of prednisone or equivalent except for management of adverse events and CNS metastases during the course of the study. Subjects requiring intermittent use of bronchodilators or local steroid injections are not excluded.
4. Active herpes infection, herpes requiring chronic anti-herpetic therapy, or complications of prior herpetic infection (such as keratitis or encephalitis)
5. Chronic use of immunosuppressants or steroids (defined as prednisone 10mg/day or equivalent)
6. Clinically active cerebral metastases
7. History or evidence of melanoma associated with immunodeficiency states
8. History of other malignancy within prior 24 months with the exception of breast or bladder carcinoma in situ, and non-melanomatous skin cancer

Contacts and Locations

Contacts

Contact: Ari VanderWalde, MD; 901-683-0055 ext 63015; avanderw@westclinic.com

Contact: Curry Luttrell; 901-683-0055 ext 63014; cluttrell@westclinic.com

Locations

United States, Tennessee

West Cancer Center; Recruiting

Germantown, Tennessee, United States, 38138

Contact: Ari VanderWalde, MD, MPH 901-683-0055 ext 63015 avanderw@westclinic.com

Contact: Nibedita Chakraborty 901-683-0055 ext 63023 nchakraborty@westclinic.com

Sponsors and Collaborators

West Cancer Center

University of Tennessee Health Science Center

Amgen

More Information

• Responsible Party: West Cancer Center
• ClinicalTrials.gov Identifier: NCT03088176
• Other Study ID Numbers: WCC20149189
• First Posted: March 23, 2017
• Last Update Posted: October 1, 2019
• Last Verified: September 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No
• Plan Description: Data will be de-identified before publication or sharing with external entities or researchers

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Keywords provided by West Cancer Center:

Melanoma; BRAF inhibitor; Intratumoral injection; Talimogene laherparepvec; MEK inhibitor; dabrafenib; trametinib

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; Trametinib; Dabrafenib; Talimogene laherparepvec; Antineoplastic Agents; Protein Kinase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents, Immunological