Neoadjuvant Use of Talimogene Laherparepvec and BRAF/MEK Inhibitor for Advanced Nodal BRAF Mutant Melanoma

NCT03972046 | Withdrawn Phase 2 FDA Drug

• 2 other identifiers: 17-08620177504
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

Brief Summary

This study will investigate whether the use of talimogene laherparepvec (T-VEC) in combination with BRAF/MEK inhibitor will result in durable regional and distant recurrence free survival in the neoadjuvant setting for treatment of advanced nodal BRAF mutant melanoma.

Conditions

Melanoma (Skin); Melanoma Stage IIIb-IVM1a; Metastasis Skin; Tumor Skin; BRAF Gene Mutation

Keywords

T-VEC; BRAF/MEK inhibition; Melanoma; Nodal metastasis; Neoadjuvant treatment; BRAF mutant

Outcome Measures

Primary Outcomes (1)

• Rate of recurrence-free survival

  1 year

Secondary Outcomes (17)

• Rate of melanoma specific survival

  1 year

• Rate of melanoma specific survival

  2 years

• Rate of melanoma specific survival

  3 years

• Rate of distant metastatic free survival

  1 year

• Rate of distant metastatic free survival

  2 years

Study Arms (1)

T-Vec + BRAF/MEK

EXPERIMENTAL

Participants will begin taking the following 3 medications: BRAF Inhibitor dabrafenib 150 mg by mouth twice a day; MEK inhibitor trametinib 2 mg by mouth once a day; Talimogene laherparepvec (T-Vec) up to 4mL subcutaneous injection (Dose #1: 10\^6 PFU/mL; Dose #2: 10\^8 PFU/mL 21 (+3) days after first dose; Subsequent doses: 10\^8 PFU/mL every 14 (+/-3) days). Dosing to continue for at least 3 months, or up to 6 months if no plateau in response. May stop earlier than 3 months at physician discretion depending on side effects and response. Ultrasound of tumor nodal basin(s) monthly. Labs every 4 weeks: CBC with differential, CMP, LDH CT of chest/abdomen/pelvis every 3 months. PET CT or brain MRI as needed at discretion of the investigator. Manual tumor measurement in office prior to each injection.

Drug: Talimogene laherparepvec (T-Vec); Drug: Dabrafenib (BRAF Inhibitor); Drug: Trametinib (MEK Inhibitor)

Interventions

Talimogene laherparepvec (T-Vec) DRUG

Talimogene laherparepvec (T-Vec) up to 4mL subcutaneous injection

T-Vec + BRAF/MEK

Dabrafenib (BRAF Inhibitor) DRUG

Dabrafenib (BRAF Inhibitor) 150 mg by mouth twice a day

T-Vec + BRAF/MEK

Trametinib (MEK Inhibitor) DRUG

Trametinib (MEK Inhibitor) 2 mg by mouth once a day

T-Vec + BRAF/MEK

Eligibility Criteria

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

You may qualify if:

• Age ≥ 18
• Malignant melanoma Stage IIIb-IVM1a patients.
• Primary or recurrent disease.
• Cutaneous primary melanoma or unknown primary.
• Measurable disease as evidenced by:
• At least one lesion measuring greater than or equal to 10 mm on CT, ultrasound, or physical exam
• A conglomerate of superficial lesions measuring which in aggregate have a total diameter of 10 mm
• Injectable disease
• Palpable regional metastasis at the time of initial presentation or with regional recurrence
• Tumor(s) with BRAF mutation
• ECOG 0,1,2
• Life expectancy \> 2 years in the opinion of the investigator
• Able to provide written informed consent
• Adequate organ function based on most recent labs (according to investigator discretion), defined as follows:
• Hematological: Absolute neutrophil count ≥ 1500/mm3 (1.5x109/L); Platelet count ≥ 75,000/mm3 (7.5x109/L); Hemoglobin ≥ 8 g/dL (without need for hematopoietic growth factor or transfusion support)

You may not qualify if:

• BRAF wild type tumor
• M1b and M1c disease
• Clinically active cerebral metastases, bony metastases, visceral metastases
• Mucosal or ocular primary disease
• Known active central nervous system (CNS) metastases. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids \>10 mg/day of prednisone or equivalent. The exception does not include carcinomatosus meningitis which is excluded regardless of clinical stability.
• History or evidence of active autoimmune disease that requires systemic treatment (ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
• Evidence of clinically significant immunosuppression such as the following:
• Primary immunodeficiency state such as Severe Combined Immunodeficiency Disease.
• Concurrent opportunistic infection.
• Receiving systemic immunosuppressive therapy (\> 2 weeks) including oral steroid doses \> 10 mg/day of prednisone or equivalent within 7 days prior to enrollment.
• Active herpetic skin lesions or prior complications of HSV-1 infection (e.g., herpetic keratitis or encephalitis).
• Requires intermittent or chronic systemic (intravenous or oral) treatment with an antiherpetic drug (e.g., acyclovir), other than intermittent topical use.
• Previous treatment with talimogene laherparepvec or any other oncolytic virus.
• Previous treatment with a BRAF or MEK inhibitor
• Prior therapy with tumor vaccine.

Sponsors & Collaborators

• TriHealth Inc.: lead
• TriHealth Cancer Institute: collaborator
• TriHealth Surgical Institute: collaborator
• TriHealth Ultrasound Department: collaborator
• Bethesda North TriHealth Hospital: collaborator
• Good Samaritan TriHealth Hospital: collaborator

Study Sites (1)

TriHealth Cancer Institute - Kenwood

Cincinnati, Ohio, 45236, United States

Location

Related Publications (10)

• Flaherty KT, Infante JR, Daud A, Gonzalez R, Kefford RF, Sosman J, Hamid O, Schuchter L, Cebon J, Ibrahim N, Kudchadkar R, Burris HA 3rd, Falchook G, Algazi A, Lewis K, Long GV, Puzanov I, Lebowitz P, Singh A, Little S, Sun P, Allred A, Ouellet D, Kim KB, Patel K, Weber J. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med. 2012 Nov 1;367(18):1694-703. doi: 10.1056/NEJMoa1210093. Epub 2012 Sep 29.

  PMID: 23020132 BACKGROUND

• Andtbacka RH, Ross M, Puzanov I, Milhem M, Collichio F, Delman KA, Amatruda T, Zager JS, Cranmer L, Hsueh E, Chen L, Shilkrut M, Kaufman HL. Patterns of Clinical Response with Talimogene Laherparepvec (T-VEC) in Patients with Melanoma Treated in the OPTiM Phase III Clinical Trial. Ann Surg Oncol. 2016 Dec;23(13):4169-4177. doi: 10.1245/s10434-016-5286-0. Epub 2016 Jun 24.

  PMID: 27342831 BACKGROUND

• Andtbacka RH, Kaufman HL, Collichio F, Amatruda T, Senzer N, Chesney J, Delman KA, Spitler LE, Puzanov I, Agarwala SS, Milhem M, Cranmer L, Curti B, Lewis K, Ross M, Guthrie T, Linette GP, Daniels GA, Harrington K, Middleton MR, Miller WH Jr, Zager JS, Ye Y, Yao B, Li A, Doleman S, VanderWalde A, Gansert J, Coffin RS. Talimogene Laherparepvec Improves Durable Response Rate in Patients With Advanced Melanoma. J Clin Oncol. 2015 Sep 1;33(25):2780-8. doi: 10.1200/JCO.2014.58.3377. Epub 2015 May 26.

  PMID: 26014293 BACKGROUND

• Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2017. CA Cancer J Clin. 2017 Jan;67(1):7-30. doi: 10.3322/caac.21387. Epub 2017 Jan 5.

  PMID: 28055103 BACKGROUND

• Coit DG, Thompson JA, Algazi A, Andtbacka R, Bichakjian CK, Carson WE 3rd, Daniels GA, DiMaio D, Ernstoff M, Fields RC, Fleming MD, Gonzalez R, Guild V, Halpern AC, Hodi FS Jr, Joseph RW, Lange JR, Martini MC, Materin MA, Olszanski AJ, Ross MI, Salama AK, Skitzki J, Sosman J, Swetter SM, Tanabe KK, Torres-Roca JF, Trisal V, Urist MM, McMillian N, Engh A. Melanoma, Version 2.2016, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2016 Apr;14(4):450-73. doi: 10.6004/jnccn.2016.0051.

  PMID: 27059193 BACKGROUND

• Thiam A, Zhao Z, Quinn C, Barber B. Years of life lost due to metastatic melanoma in 12 countries. J Med Econ. 2016;19(3):259-64. doi: 10.3111/13696998.2015.1115764. Epub 2015 Nov 25.

  PMID: 26531249 BACKGROUND

• Solit DB, Rosen N. Resistance to BRAF inhibition in melanomas. N Engl J Med. 2011 Feb 24;364(8):772-4. doi: 10.1056/NEJMcibr1013704. No abstract available.

  PMID: 21345109 BACKGROUND

• Hauschild A, Grob JJ, Demidov LV, Jouary T, Gutzmer R, Millward M, Rutkowski P, Blank CU, Miller WH Jr, Kaempgen E, Martin-Algarra S, Karaszewska B, Mauch C, Chiarion-Sileni V, Martin AM, Swann S, Haney P, Mirakhur B, Guckert ME, Goodman V, Chapman PB. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2012 Jul 28;380(9839):358-65. doi: 10.1016/S0140-6736(12)60868-X. Epub 2012 Jun 25.

  PMID: 22735384 BACKGROUND

• Johnson AS, Crandall H, Dahlman K, Kelley MC. Preliminary results from a prospective trial of preoperative combined BRAF and MEK-targeted therapy in advanced BRAF mutation-positive melanoma. J Am Coll Surg. 2015 Apr;220(4):581-93.e1. doi: 10.1016/j.jamcollsurg.2014.12.057. Epub 2015 Jan 30.

  PMID: 25797743 BACKGROUND

• Grigg C, Blake Z, Gartrell R, Sacher A, Taback B, Saenger Y. Talimogene laherparepvec (T-Vec) for the treatment of melanoma and other cancers. Semin Oncol. 2016 Dec;43(6):638-646. doi: 10.1053/j.seminoncol.2016.10.005. Epub 2016 Oct 27.

  PMID: 28061981 BACKGROUND

MeSH Terms

Conditions

Melanoma; Skin Neoplasms

Interventions

talimogene laherparepvec; dabrafenib; trametinib

Condition Hierarchy (Ancestors)

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

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Patients, aged 18+, seen at the TriHealth Cancer Institute and/or TriHealth Surgical Institute with a palpable regional melanoma metastasis at the time of initial presentation or with regional recurrence and tumors with a BRAF mutation will be considered for participation in this study.

Study Record Dates

• First Submitted: May 31, 2019
• First Posted: June 3, 2019
• Study Start: June 24, 2019
• Primary Completion: February 3, 2020
• Study Completion: February 3, 2020
• Last Updated: October 19, 2020

Record last verified: 2020-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)