Sonidegib and Pembrolizumab in Treating Patients With Advanced Solid Tumors

March 22, 2024 updated by: Mayo Clinic

Phase I Trial of Sonidegib and Pembrolizumab in Advanced Solid Tumors

This phase I trial studies the best dose of sonidegib when given together with pembrolizumab and to see how well they work in treating patients with solid tumor that has spread to other places in the body (advanced). Sonidegib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving sonidegib and pembrolizumab may work better than standard treatment in treating patients with advanced solid tumors.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) of sonidegib in combination with pembrolizumab in participants with advanced solid tumors as part of the dose escalation phase. (Part A) II. To estimate the response rate of sonidegib in combination with pembrolizumab in participants with non-small cell lung cancer (NSCLC) or head and neck squamous cell carcinoma (HNSCC) as part of the expansion cohort based on Response Evaluation Criteria in Solid Tumors (RECIST) criteria. (Part B)

SECONDARY OBJECTIVES:

I. To characterize the safety profile and tolerability of sonidegib and pembrolizumab.

II. To obtain preliminary estimates of efficacy as measured by response rate (based on RECIST criteria), disease control rate at 6 months, duration of response, overall survival (OS), and progression free survival (PFS) of sonidegib and pembrolizumab in patients with selected advanced solid tumors.

CORRELATIVE RESEARCH OBJECTIVE:

I. To estimate the immunologic effects of sonidegib and pembrolizumab by investigating the changes in circulating tumor cells, immune cell markers, cytokines, and soluble PD-L1 in blood.

OUTLINE: This is a dose-escalation study of sonidegib.

Patients receive sonidegib orally (PO) once daily (QD) on days 1-8 and pembrolizumab intravenously (IV) over 30 minutes on day 8. Treatment repeats every 21 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up within 30 days.

Study Type

Interventional

Enrollment (Estimated)

45

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Arizona
      • Scottsdale, Arizona, United States, 85259
        • Completed
        • Mayo Clinic in Arizona
    • Florida
      • Jacksonville, Florida, United States, 32224-9980
        • Recruiting
        • Mayo Clinic in Florida
        • Principal Investigator:
          • Yanyan Lou, M.D.
        • Contact:
    • Minnesota
      • Rochester, Minnesota, United States, 55905
        • Recruiting
        • Mayo Clinic in Rochester
        • Contact:
        • Principal Investigator:
          • Mojun Zhu, M.D.

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Age >= 18 years
  • Measurable disease by RECIST criteria.
  • Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1.
  • Hemoglobin >= 9.0 g/dL (obtained =< 28 days prior to registration).
  • Absolute neutrophil count (ANC) >= 1000/mm^3 (obtained =< 28 days prior to registration).
  • Platelet count >= 100,000/mm^3 (obtained =< 28 days prior to registration).
  • Total bilirubin =< 1.5 x upper limit of normal (ULN) OR direct bilirubin =< ULN (obtained =< 28 days prior to registration).
  • Alanine aminotransferase (ALT) and aspartate transaminase (AST) =< 2.5 x ULN (=< 5 x ULN for patients with liver involvement) (obtained =< 28 days prior to registration).
  • Creatinine phosphokinase (CK) =< 2.5 x ULN (obtained =< 28 days prior to registration).
  • Serum creatinine =< 1.5 x ULN or calculated creatinine clearance >= 50 ml/min using the Cockcroft-Gault formula (obtained =< 28 days prior to registration).
  • Negative serum pregnancy test done =< 7 days prior to registration, for persons of childbearing potential only.
  • Patients of childbearing potential agree to use two forms of medically approved contraception while taking the study drug and for 20 months following the last dose of study drug. Patients with partners of childbearing potential agree to use condoms, even after vasectomy, to avoid potential drug exposure to partner during study drug and for 8 months following the last dose of study drug.
  • Willing to return to enrolling institution for follow-up (during the active monitoring phase of the study).
  • Willing to provide blood samples for correlative research purposes.
  • Must be able to swallow capsules and have no significant impairment in gastrointestinal absorption.
  • Willing and able to provide informed consent.

  • PART A (DOSE ESCALATION): Patient must satisfy all subsets in one of the following:

    • Patients with NSCLC.

      • Pathologically confirmed metastatic non-small cell lung cancer (NSCLC).
      • Patients with EGFR, ALK, or BRAF genomic abnormalities must have also received and progressed on prior Food and Drug Administration (FDA)-approved targeted therapies

    • Melanoma.

      • Unresectable or metastatic melanoma.

        • NOTE: Previous treatment using PD-1/PD-L1 checkpoint inhibitors is allowed.

    • Head and neck squamous cell cancer (HNSCC):

      • Recurrent or metastatic HNSCC with disease progression on or after prior platinum-containing chemotherapy.

        • NOTE: Previous treatment using PD-1/PD-L1 checkpoint inhibitors is allowed.

    • Urothelial carcinoma (locally advanced or metastatic).

      • Newly diagnosed cisplatin ineligible patients. OR
      • Progression during or within 12 months of treatment with platinum-containing agent.

    • Microsatellite instability-high (MSI-H) cancer.

      • Unresectable or metastatic solid tumors that progressed on prior treatment and are MSI-H or mismatch repair deficient.
      • No satisfactory alternative treatment options available. For colorectal cancer, must have progressed following treatment with fluoropyramidine, oxaliplatin, and irinotecan.

    • Gastric or gastroesophageal junction adenocarcinoma

      • Locally advanced or metastatic tumors that express PD-L1 as evidenced by a combined positive score (>= 1) using the PD-L1 immunohistochemistry (IHC) 223C pharmDx test (Dako).
      • Disease progression on 2 or more prior systemic therapies.

  • PART B (DOSE EXPANSION) COHORT A: Recurrent or metastatic HNSCC

    • Pathologically confirmed recurrent or metastatic HNSCC

    • Disease progression on or after platinum-containing chemotherapy

      • NOTE: Previous treatment using PD-1/PD-L1 checkpoint inhibitors is allowed.

  • PART B ( DOSE EXPANSION) COHORT B: Refractory NSCLC.

    • Pathologically confirmed metastatic non-small cell lung cancer (NSCLC).

    • Disease progression on >= 1 prior line of systemic therapy.

      • NOTE: Previous treatment using PD-1/PD-L1 checkpoint inhibitors is allowed.
    • Patients with EGFR, ALK, or BRAF genomic abnormalities must have also received and progressed on prior FDA-approved targeted therapies.

Exclusion Criteria:

  • Any of the following because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects:

    • Pregnant persons.
    • Nursing persons.
    • Persons of childbearing potential and with partners of childbearing potential who are unwilling to employ adequate contraception.
  • CTCAE >= grade 3 treatment-emergent adverse event (TEAE) to prior checkpoint inhibitor, TEAE requiring systemic corticosteroids, or permanent treatment discontinuation due to toxicity.
  • Neuromuscular disorders (e.g. inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis and spinal muscular atrophy), or a history of rhabdomyolysis.

  • Concomitant treatment with drugs that are recognized to cause rhabdomyolysis, including statins.

    • NOTE: Patients taking such medications need to be discontinued at least 2 weeks prior to starting sonidegib treatment. If an agent to control lipids is required, pravastatin may be given with caution.
  • Receiving strong inhibitors or inducers of CYP3A4/5, moderate inducers of CYP3A4, and/or grapefruit/grapefruit juice or starfruit products that cannot be discontinued before starting treatment with sonidegib.

NOTE: Medications that are strong CYP3A4/5 inhibitors or inducers, moderate inducers of CYP3A4, and grapefruit/grapefruit juice/starfruit products should be discontinued at least 4 weeks prior to starting treatment with sonidegib.

  • Active autoimmune diseases that have required systemic treatment modifications within the past 3 months or that require chronic systemic steroids or immunosuppressive agents.
  • Requirement for systemic corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications =< 14 days prior to registration.

NOTE: Inhaled or topical steroids, and adrenal replacement steroid doses >10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease.

  • Life expectancy < 3 months.
  • Central nervous system metastases that are untreated, symptomatic, or require steroids.

NOTE: Patients with history of stable treated brain metastases are eligible. Stable treated metastases are defined as follows:

  • No evidence of progression for >= 8 weeks on brain imaging (either magnetic resonance imaging [MRI] or computed tomography [CT] scan).
  • No corticosteroid use for brain metastases for >= 2 weeks before randomization.

  • >= 8 weeks from completion of definitive treatment for brain metastases.

    • Any of the following prior therapies:
  • Major surgery =< 4 weeks prior to registration.
  • Received any experimental drugs or anti-neoplastic therapy =< 4 weeks prior to receiving the first dose of study treatment

  • Received a live vaccine =< 30 days prior to registration

    • Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens.
    • Ongoing AE due to prior treatment not recovered to =< grade 1 per CTCAE or baseline unless clinically nonsignificant and/or stable with supportive therapy

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Treatment (sonidegib, pembrolizumab)
Patients receive sonidegib PO QD on days 1-8, and pembrolizumab IV over 30 minutes on day 8. Treatment repeats every 21 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity.
Biological: Pembrolizumab
Given IV
Other Names:
  • Keytruda
  • MK-3475
  • Lambrolizumab
  • SCH 900475
Drug: Sonidegib
Given PO
Other Names:
  • LDE225
  • LDE-225
  • Odomzo
  • Smoothened Antagonist LDE225
  • Erismodegib

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Maximum tolerated dose (MTD) of sonidegib in combination with pembrolizumab (Part A)
Time Frame: Up to 21 days
MTD is defined as the dose level below the lowest dose that induces dose- limiting toxicity (DLT) in at least one-third of patients. Three patients will be treated at a given dose level combination and observed for at least 21 days from start of treatment to assess toxicity.
Up to 21 days
Response rate of sonidegib in combination with pembrolizumab (Part B)
Time Frame: Up to 30 days post treatment
Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria.
Up to 30 days post treatment

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Incidence of adverse events
Time Frame: Up to 30 days post treatment
Assessed by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0. Number of severity of all adverse events will be tabulated and summarized. The grade 3+ adverse events will also be described and summarized in a similar fashion. Overall toxicity incidence as well as toxicity profiles by dose level and patient will be explored and summarized. Frequency distributions, graphical techniques and other descriptive measures will form the basis of these analyses.
Up to 30 days post treatment
Response profile
Time Frame: Up to 30 days post treatment
Responses will be calculated based on RECIST 1.1 for this study. Best response is defined to be the best objective status recorded from the start of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started). Responses will be summarized by simple descriptive summary statistics delineating complete and partial responses as well as stable and progressive disease in this patient population.
Up to 30 days post treatment
Duration of response (DOR)
Time Frame: From the date on which an objective response is first determined until the first date on which radiographic disease progression is determined, assessed up to 30 days
Determined only for patients with confirmed response. Participants who achieve a confirmed objective response who have not experienced radiographic or clinical progression will be censored at the date of the last available post-baseline evaluable tumor assessment.
From the date on which an objective response is first determined until the first date on which radiographic disease progression is determined, assessed up to 30 days
Disease control rate (DCR)
Time Frame: At 6 months
Assessed by RECIST v1.1. DCR defined as proportion of participants who achieve complete response (CR), partial response (PR), or stable disease and do not experience subsequent radiographic progressive disease for >= 6 months from the time of treatment initiation.
At 6 months
Overall survival (OS)
Time Frame: From study entry to death from any cause, assessed up to 30 days post treatment
Will be estimated using Kaplan-Meier method.
From study entry to death from any cause, assessed up to 30 days post treatment
Progression-free survival (PFS)
Time Frame: From study entry to the first of either disease progression or death from any cause, assessed up to 30 days post treatment
Disease progression will be determined based on RECIST 1.1 criteria. PFS will be estimated using the Kaplan-Meier method.
From study entry to the first of either disease progression or death from any cause, assessed up to 30 days post treatment

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Changes in immune cell markers, cytokines, and soluble PD-L1
Time Frame: Baseline up to 30 days post treatment
Will estimate the immunologic effects of sonidegib and pembrolizumab by investigating the changes in immune cell markers, cytokines, and soluble PD-L1 in blood. These changes will be assessed over time and correlated with clinical data as well in an exploratory and hypothesis generating fashion.
Baseline up to 30 days post treatment
Levels of Bcl-2 interacting mediator of cell death (BIM)
Time Frame: At baseline
Assessed by flow cytometry.
At baseline
Level of serum soluble PDL-1
Time Frame: At baseline
At baseline

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Mayo Clinic

Collaborators

National Cancer Institute (NCI)

Investigators

  • Principal Investigator: Mojun Zhu, M.D., Mayo Clinic in Rochester

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

February 13, 2020

Primary Completion (Estimated)

July 1, 2024

Study Completion (Estimated)

July 1, 2024

Study Registration Dates

First Submitted

July 2, 2019

First Submitted That Met QC Criteria

July 2, 2019

First Posted (Actual)

July 5, 2019

Study Record Updates

Last Update Posted (Actual)

March 26, 2024

Last Update Submitted That Met QC Criteria

March 22, 2024

Last Verified

March 1, 2024

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • MC1718 (Mayo Clinic in Rochester)
  • NCI-2019-04098 (Registry Identifier: CTRP (Clinical Trial Reporting Program))
  • 18-007218 (Other Identifier: Mayo Clinic Institutional Review Board)

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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