Androgen Deprivation Therapy (ADT) and Pembrolizumab for Advanced Stage Androgen Receptor-positive Salivary Gland Carcinoma

• ClinicalTrials.gov Identifier: NCT03942653
• Recruitment Status: Recruiting
• First Posted: May 8, 2019
• Last Update Posted: March 15, 2023
• Sponsor: Manish Patel
• Collaborator: Merck Sharp & Dohme LLC
• Information provided by (Responsible Party): Manish Patel, Big Ten Cancer Research Consortium

Study Description

Brief Summary:

A Phase II, multi-center, single-arm, non-blinded study combining androgen deprivation therapy (ADT) and pembrolizumab for patients with metastatic or locally recurrent androgen receptor-positive salivary gland carcinoma, not amenable to surgery or radiation.

Condition or disease	Intervention/treatment	Phase
Salivary Gland Carcinoma	Drug: Goserelin Acetate; Drug: Pembrolizumab	Phase 2

Detailed Description:

This is a Phase II multi-center, single-arm, non-blinded study combining androgen deprivation therapy (ADT) and pembrolizumab for patients with metastatic or locally recurrent androgen receptor-positive salivary gland carcinoma, not amenable to surgery or radiation. Eligible patients will include both those with no prior systemic therapy and those who have failed prior systemic therapy. Patients who have received previous ADT or immunotherapy will be excluded.

ADT will consist of goserelin acetate every 4 weeks with the first injection given approximately 2 weeks prior to the first dose of pembrolizumab. Pembrolizumab 200 mg will be given on day 1 of 21-day cycles, starting 2 weeks after initiation of goserelin acetate. Each 21-day period is considered a treatment cycle with therapy continuing for up to 35 cycles, until disease progression, significant toxicity, or patient refusal. Except for fatigue, we do not expect overlapping toxicities with pembrolizumab and ADT, thus the starting doses will be the FDA-approved doses.

This study will use a Simon 2-stage phase II trial design. The first stage of the Simon 2-stage design will have a sample size of nine patients. If at least two patients have an objective response by RECIST 1.1 then enrollment will proceed to stage 2 with an additional 11 patients, to a goal of 20 patients. If less than 4 patients out of 20 respond, then the combination treatment will be rejected.

Patients will be staged with CT of neck, chest, abdomen, and pelvis at baseline and every 12 weeks while on study. Treatment with both ADT and pembrolizumab will continue until disease progression or intolerable side effects.

Archival tumor biopsy tissue must be available at baseline to evaluate for expression of androgen receptor (AR), PD-L1, and tumor-infiltrating lymphocytes (TIL). An optional biopsy will be performed after 4 doses of pembrolizumab to evaluate immune response to combined therapy.

Blood will be collected at baseline, cycle 1 day 1, cycle 2 day 1 and cycle 3 day 1 to evaluate for change in lymphocyte subsets by flow cytometry.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 20 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Trial of Androgen Deprivation Therapy (ADT) and Pembrolizumab for Advanced Stage Androgen Receptor-positive Salivary Gland Carcinoma: Big Ten Cancer Research Consortium BTCRC-HN17-111
• Actual Study Start Date: May 30, 2019
• Estimated Primary Completion Date: July 2023
• Estimated Study Completion Date: January 2024

Arms and Interventions

Arm	Intervention/treatment
Experimental: Goserelin Acetate + Pembrolizumab; Goserelin Acetate, 3.6 mg, every four weeks, SQ Pembrolizumab, 200mg, every three weeks, IV	Drug: Goserelin Acetate; Goserelin Acetate, SQ, Q4W; Drug: Pembrolizumab; Pembrolizumab, IV, Q3W

Outcome Measures

Primary Outcome Measures :

1. Objective Response Rate [ Time Frame: 35 months ]
   Objective response rate to therapy (complete and partial responses) at 3 month intervals after beginning goserelin and pembrolizumab based on Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1)

Secondary Outcome Measures :

1. Progression Free Survival [ Time Frame: 12 Months ]
   Determine progression free survival (PFS) at 12 months, according to RECIST 1.1 criteria
2. Disease Control Rate [ Time Frame: 35 Months ]
   Disease control rate as defined by stable disease plus objective response (SD+PR+CR), according to RECIST 1.1 criteria
3. Assess Adverse Events [ Time Frame: 35 months ]
   To evaluate the safety and tolerability of pembrolizumab when given with goserelin, grade 3,4,5 adverse events will be summarized according to CTCAE v5 criteria.
4. Overall Survival [ Time Frame: 12 Months ]
   Determine overall survival (OS) at 12 months, according to RECIST 1.1 criteria

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:

• Written informed consent and HIPAA authorization for release of personal health information. NOTE: HIPAA authorization may be included in the informed consent or obtained separately.
• Age ≥ 18 years at the time of consent.
• Locally advanced, recurrent, or metastatic salivary gland carcinoma that is not amenable to curative surgery or radiation
• ECOG Performance Status of 0 or 1 within 28 days prior to registration.
• Local, pathologic testing of androgen receptor-positive salivary gland carcinoma will be performed as standard of care. Archival tissue must be available for central confirmation of androgen receptor-positive disease and for correlative studies. AR positivity will be defined according to IHC staining of tumor tissue with at least 20% of tumor staining positive with moderate intensity (1+ or greater).
• Measurable disease according to RECIST v1.1 for solid tumors within 28 days prior to registration.
• For patients who have been treated with prior therapy, patients must have documented progression of disease on their prior therapy for entry into the study.
• Patients with prior chemotherapy, radiation, or surgery as part of curative intent therapy are allowed. Any number of prior lines of systemic therapy is permitted for entry into this study so long as prior therapy did not include anti-androgen therapy or immune checkpoint blockade.
• If prior cancer treatment, the subject must have recovered from toxic effects of prior cancer treatment (other than alopecia) to ≤ Grade 1.

• Adequate organ function as defined below; all screening labs to be obtained within 28 days prior to registration.

  • Absolute neutrophil count (ANC) ≥1500/µL
  • Platelets ≥100,000/µL
  • Hemoglobin ≥9.0 g/dL or ≥5.6 mmol/L

  • Creatinine (Cr) OR Measured or calculated creatinine clearance (GFR can also be used in place of Cr or creatinine clearance) ≤1.5 × ULN OR

    ≥30 mL/min for participant with creatinine levels >1.5 × institutional ULN

  • Total bilirubin ≤1.5 ×ULN OR direct bilirubin ≤ULN for participants with total bilirubin levels >1.5 × ULN
  • AST (SGOT) and ALT (SGPT) ≤2.5 × ULN (≤5 × ULN for participants with liver metastases) o International normalized ratio (INR) OR prothrombin time (PT) & aPTT ≤1.5 × ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants
• A male participant must agree to use contraception during the treatment period and for at least 8 months after the last dose of study treatment and refrain from donating sperm during this period.
• Females of childbearing potential must have a negative serum pregnancy test within 72 hours prior to registration. NOTE: Females are considered of child bearing potential unless they are surgically sterile (have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are naturally postmenopausal for at least 12 consecutive months
• Females of childbearing potential and males with partners of childbearing potential must be willing to abstain from heterosexual activity or to use a highly effect form of contraception from the time of informed consent until 8 months after treatment discontinuation.
• As determined by the enrolling physician or protocol designee, ability of the subject to understand and comply with study procedures for the entire length of the study

Exclusion Criteria:

• Women of childbearing age with a positive serum pregnancy test within 72 hours prior to study registration.
• Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX40, CD137).
• Has received prior androgen deprivation therapy including orchiectomy, gonadotropin-releasing hormone (GnRH) agonists/antagonists, androgen receptor blocker, abiraterone, or enzalutamide.
• Has received prior systemic anti-cancer therapy including investigational agents within 14 days prior to registration.
• Has had an allogenic tissue or solid organ transplant.
• Has received prior palliative radiotherapy within 7 days of start of study treatment. Participants must have recovered from all radiation-related toxicities and require less than 10mg of prednisone (or equivalent corticosteroid) daily.
• Has received a live vaccine or live-attenuated vaccine within 28 days prior to the first dose of study drug. Administration of killed vaccines is allowed.
• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug.
• Has a known additional malignancy that is progressing or has required active treatment within the past 2 years. Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (e.g. breast ductal carcinoma in situ, cervical cancer in situ) that have undergone potentially curative therapy are not excluded.
• Has known active CNS metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable, i.e. without evidence of progression for at least 14 days by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable, and without requirement of steroid treatment for at least 14 days prior to first dose of study treatment.
• Has ≥Grade 3 hypersensitivity to pembrolizumab and/or any of its excipients.
• Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg, levothyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
• Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
• Has an active infection requiring systemic therapy.
• Has a known history of Human Immunodeficiency Virus (HIV).
• Has a known history of active TB (Bacillus Tuberculosis).
• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject's participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
• Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
• Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of trial treatment.

Contacts and Locations

Contacts

Contact: Manish Patel, MD; 6126246940; Patel069@umn.edu

Contact: Brittany Brugh; 317-634-5842 ext 13; bbrugh@hoosiercancer.org

Locations

United States, Illinois

Northwestern University Feinberg School of Medicine; Recruiting

Chicago, Illinois, United States, 60611

Contact: Catie Humphreys 312-695-1355 catherine-collins@northwestern.edu

Principal Investigator: Victoria Villaflor, MD

University of Illinois Cancer Center; Recruiting

Chicago, Illinois, United States, 60612

Contact: Lauren Talasnik 312-996-6275 talasnik@uic.edu

Principal Investigator: Lawrence Feldman, MD

United States, Iowa

University of Iowa Hospitals and Clinics; Recruiting

Iowa City, Iowa, United States, 52242

Contact: Marian Anderson 319-353-4578 marian-andersen@uiowa.edu

Principal Investigator: Douglas Laux, MD

United States, Maryland

Univeristy of Maryland; Recruiting

Baltimore, Maryland, United States, 21201

Contact: Amelia Barkman 410-706-3761 AmeliaSchmidt@umm.edu

Sub-Investigator: Ranee Mehra, MD

United States, Michigan

University of Michigan Health System; Recruiting

Ann Arbor, Michigan, United States, 48109

Contact: Dawud Ellayan 734-615-1749 dellayan@med.umich.edu

Principal Investigator: Francis Worden, MD

United States, Minnesota

University of Minnesota: Masonic Cancer Center; Recruiting

Minneapolis, Minnesota, United States, 55455

Contact: Manish Patel, M.D. 612-624-6940 Patel069@umn.edu

United States, Wisconsin

University of Wisconsin; Recruiting

Madison, Wisconsin, United States, 53705

Contact: Sarah Stewart 608-263-7898 slstewart@wisc.edu

Principal Investigator: Justin Bruce, MD

Sponsors and Collaborators

Manish Patel

Merck Sharp & Dohme LLC

Investigators

• Principal Investigator: Manish Patel, MD; University of Minnesota

More Information

• Responsible Party: Manish Patel, Sponsor-Investigator, Big Ten Cancer Research Consortium
• ClinicalTrials.gov Identifier: NCT03942653
• Other Study ID Numbers: BTCRC-HN17-111
• First Posted: May 8, 2019
• Last Update Posted: March 15, 2023
• Last Verified: March 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• 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

Additional relevant MeSH terms:

Carcinoma; Salivary Gland Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Mouth Neoplasms; Head and Neck Neoplasms; Neoplasms by Site; Mouth Diseases; Stomatognathic Diseases; Salivary Gland Diseases; Pembrolizumab; Goserelin; Antineoplastic Agents, Immunological; Antineoplastic Agents; Immune Checkpoint Inhibitors; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents, Hormonal