Pre-operative Mocetinostat (MGCD0103) and Durvalumab (MEDI4736) (PRIMED) for Squamous Cell Carcinoma of the Oral Cavity

NCT02993991 | Withdrawn Phase 1 FDA Drug

• 1 other identifier: PRIMED-001
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

Brief Summary

This is a Phase 1 Window of Opportunity study to evaluate the pharmacodynamic and immune effects of pre-operative therapy with Mocetinostat and Durvalumab on patients with squamous cell carcinoma of the oral cavity.

Conditions

Squamous Cell Carcinoma, Head And Neck; Squamous Cell Carcinoma Mouth; Resectable Squamous Cell Carcinoma of Oral Cavity

Outcome Measures

Primary Outcomes (2)

• Pharmacodynamic effects with biomarker analyses (Tumor PD-L1 by IHC; Density of peri-tumoral and intra-tumoral CD3, CD4 and CD8-positive lymphocytes; Serum pro-inflammatory cytokines and chemokines)

  3 years

• Immune effects with biomarker analyses (Tumor PD-L1 by IHC; Density of peri-tumoral and intra-tumoral CD3, CD4 and CD8-positive lymphocytes; Serum pro-inflammatory cytokines and chemokines)

  3 years

Secondary Outcomes (6)

• Toxicities as per NCI CTCAE v4.1

  3 years

• Rate of completion of surgery within the initially planned window as per RECIST v1.1

  3 years

• Rate of disease progression as per RECIST v1.1 during the pre-operative treatment period

  3 years

• Rate of post-operative complications as per NCI CTCAE v4.1

  3 years

• Optimal biologically active dose of mocetinostat (Correlation of tumor and serum-based assessments with mocetinostat dose levels)

  3 years

Other Outcomes (2)

• Dynamic changes in immune cell activation and/or suppression using flow cytometry and DNA/RNA sequencing (tumor and immune cell genome and trascriptome analysis)

  3 years

• Dynamic changes in intratumoral hypoxia with pre-operative mocetinostat and durvalumab therapy using 18FAZA PET

  3 years

Study Arms (1)

Mocetinostat and Durvalumab

EXPERIMENTAL

Patients will start therapy with mocetinostat within 10 days of study enrollment. Mocetinostat will be given in 2 dose levels (n = 6 evaluable patients each) of 70mg three-times weekly and 90mg three-times weekly for 2 weeks. Durvalumab will be given as a single infusion at a dose of 1500mg, over a period of 1-hour, on day 8 of the study.

Drug: Mocetinostat; Biological: Durvalumab

Interventions

Mocetinostat DRUG

Mocetinostat (MGCD0103) is a potent small molecule HDAC inhibitor that targets human HDAC isoforms. It is an orally bioavailable, second generation benzamide inhibitor of HDAC 1, 2, 3 and 11 with broad spectrum antitumor activity in vitro and in vivo.

Also known as: MGCD0103

Mocetinostat and Durvalumab

Durvalumab BIOLOGICAL

Durvalumab is a human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody directed against human PD-L1. It is selective for recombinant PD-L1 and blocks the binding of recombinant PD-L1 to the PD-1 and CD80 receptors.

Also known as: MEDI4736

Mocetinostat and Durvalumab

Eligibility Criteria

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

You may qualify if:

• Signed written and voluntary informed consent.
• Patient must be willing and able to comply with scheduled visits, treatment plan, laboratory tests and other study procedures.
• Age \> 18 years, male or female. Disease characteristics
• Patient must be diagnosed with histologically confirmed squamous cell carcinoma of the oral cavity (SCCOC) (floor of mouth, anterior 2/3 tongue, buccal mucosa, upper and lower gingiva, and retromolar trigone) considered resectable by the head and neck surgical rounds (T2-4a, N0-2, M0; without evidence of distant metastasis).
• Patient must be willing and able to provide up to 2 fresh tumor biopsies for histopathological and biomarker evaluation; first as pre-treatment baseline, and the second after treatment with mocetinostat but prior to treatment with durvalumab.
• Patients who decline an in-house fresh pre-treatment tumor biopsy must give consent to provide a tumor block from an existing diagnostic primary tumor biopsy completed within 90 days of enrollment, which is of acceptable quality and quantity for analysis, as assessed by the study site correlatives team.
• No anti-neoplastic treatment is allowed between the time from obtaining baseline tumor specimen and enrollment.
• Patient characteristics
• ECOG performance status 0-1.
• Patient must have adequate organ function as determined by the following:
• \- Renal function: i. Serum creatinine \< 1.5 ULN (upper limit of normal range) or a calculated creatinine clearance of \> 50mL/min using the following formula: Creatinine clearance = \[(140-age) x wt (kg) x Constant\*\] / creatinine (umol/L)
• \*Constant = 1.23 for men, and 1.04 for women
• \- Bone marrow function (without hematopoietic growth factors or transfusion): i. Absolute neutrophil count (ANC) \> 1.5 x 109/L ii. Leukocytes \> 3.0 x 109/L iii. Hemoglobin \> 90 g/L or \> 9g/dL iv. Platelets \> 100 x 109/L
• \- Liver function: i. Total bilirubin \< ULN ii. Aspartate aminotransferase (AST/SGOT) and alanine aminotransferase (ALT/SGPT) \< 2.5 x ULN
• \- Cardiac function: i. A normal left ventricular ejection fraction (LVEF) of \> 50% and the absence of any clinically significant pericardial effusion, as evidenced by an echocardiogram performed within 4 weeks of the study commencement.

You may not qualify if:

• Primary site of head and neck carcinoma unknown, lip, hard palate, skin, or outside the oral cavity.
• Patients with tumors that invade major vessels, as shown unequivocally by imaging studies.
• For patients with tumors that do not invade major blood vessels but are within 3mm of the carotid artery or branches thereof, any anticoagulant therapy (including aspirin, non-steroidal anti-inflammatories, antiplatelet agents or other anti-coagulants) must be discontinued.
• Patients with any prior history of bleeding related to the current head and neck cancer.
• Patients with a history of gross hemoptysis (bright red blood of ½ teaspoon or more per episode of coughing) \< 3 months prior to enrollment.
• Prior or concurrent radiation therapy to tumor at site of planned resection.
• Any concurrent chemotherapy, biologic, immunologic or hormonal therapy for cancer treatment.
• Concurrent use of hormones for non-cancer-related conditions (eg, insulin for diabetes and hormone replacement therapy) is acceptable.
• Current or prior use of immunosuppressive medication within 14 days prior to starting dosing. The following are exceptions to this criteria:
• Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra-articular injection).
• Systemic corticosteroids at physiologic doses not exceeding 10 mg/day of prednisone or equivalent.
• Steroids as premedication for hypersensitivity reactions (eg, computed tomography scan premedication).
• Active or documented history of autoimmune disease within 2 years before screening, including:
• Active or prior documented inflammatory bowel disease (eg. Crohn's disease, ulcerative colitis).
• Patients with vitiligo, resolved childhood asthma/atopy, type I diabetes mellitus, Grave's disease, Hashimoto's disease, or psoriasis not requiring systemic treatment within the past 2 years, are not excluded.

Sponsors & Collaborators

• University Health Network, Toronto: lead
• Mirati Therapeutics Inc.: collaborator
• AstraZeneca: collaborator

Study Sites (1)

Princess Margaret Cancer Centre

Toronto, Ontario, M5G 2M9, Canada

Location

MeSH Terms

Conditions

Squamous Cell Carcinoma of Head and Neck

Interventions

mocetinostat; durvalumab

Condition Hierarchy (Ancestors)

Carcinoma, Squamous Cell; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Head and Neck Neoplasms; Neoplasms by Site

Study Officials

• Lillian Siu, MD

  Staff Physician and Medical Oncologist

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 1, 2016
• First Posted: December 15, 2016
• Study Start: October 10, 2017
• Primary Completion: December 21, 2017
• Study Completion: December 21, 2017
• Last Updated: December 29, 2017

Record last verified: 2017-12

Locations

CA (1)