Clinical Trials /

Sonidegib and Pembrolizumab in Treating Patients With Advanced Solid Tumors

NCT04007744

Description:

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.

Related Conditions:
  • Adenocarcinoma of the Gastroesophageal Junction
  • Head and Neck Squamous Cell Carcinoma
  • Malignant Solid Tumor
  • Melanoma
  • Non-Small Cell Lung Carcinoma
  • Pancreatic Adenocarcinoma
  • Urothelial Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Sonidegib and Pembrolizumab in Treating Patients With Advanced Solid Tumors
  • Official Title: A Phase 1 Trial of Sonidegib and Pembrolizumab in Advanced Solid Tumors

Clinical Trial IDs

  • ORG STUDY ID: MC1718
  • SECONDARY ID: NCI-2019-04098
  • SECONDARY ID: MC1718
  • SECONDARY ID: P30CA015083
  • NCT ID: NCT04007744

Conditions

  • Clinical Stage III Cutaneous Melanoma AJCC v8
  • Clinical Stage III Gastric Cancer AJCC v8
  • Clinical Stage III Gastroesophageal Junction Adenocarcinoma AJCC v8
  • Clinical Stage IV Cutaneous Melanoma AJCC v8
  • Clinical Stage IV Gastric Cancer AJCC v8
  • Clinical Stage IV Gastroesophageal Junction Adenocarcinoma AJCC v8
  • Clinical Stage IVA Gastric Cancer AJCC v8
  • Clinical Stage IVA Gastroesophageal Junction Adenocarcinoma AJCC v8
  • Clinical Stage IVB Gastric Cancer AJCC v8
  • Clinical Stage IVB Gastroesophageal Junction Adenocarcinoma AJCC v8
  • High-Frequency Microsatellite Instability
  • Locally Advanced Urothelial Carcinoma
  • Metastatic Gastric Adenocarcinoma
  • Metastatic Gastroesophageal Junction Adenocarcinoma
  • Metastatic Head and Neck Squamous Cell Carcinoma
  • Metastatic Lung Non-Small Cell Carcinoma
  • Metastatic Malignant Solid Neoplasm
  • Metastatic Melanoma
  • Metastatic Pancreatic Adenocarcinoma
  • Metastatic Urothelial Carcinoma
  • Mismatch Repair Deficiency
  • Pathologic Stage III Cutaneous Melanoma AJCC v8
  • Pathologic Stage III Gastric Cancer AJCC v8
  • Pathologic Stage III Gastroesophageal Junction Adenocarcinoma AJCC v8
  • Pathologic Stage IIIA Gastric Cancer AJCC v8
  • Pathologic Stage IIIA Gastroesophageal Junction Adenocarcinoma AJCC v8
  • Pathologic Stage IIIB Gastric Cancer AJCC v8
  • Pathologic Stage IIIB Gastroesophageal Junction Adenocarcinoma AJCC v8
  • Pathologic Stage IIIC Gastric Cancer AJCC v8
  • Pathologic Stage IV Cutaneous Melanoma AJCC v8
  • Pathologic Stage IV Gastric Cancer AJCC v8
  • Pathologic Stage IV Gastroesophageal Junction Adenocarcinoma AJCC v8
  • Pathologic Stage IVA Gastroesophageal Junction Adenocarcinoma AJCC v8
  • Pathologic Stage IVB Gastroesophageal Junction Adenocarcinoma AJCC v8
  • PD-L1 Positive
  • Progressive Disease
  • Recurrent Head and Neck Squamous Cell Carcinoma
  • Refractory Lung Non-Small Cell Carcinoma
  • Refractory Pancreatic Adenocarcinoma
  • Stage II Pancreatic Cancer AJCC v8
  • Stage IIA Pancreatic Cancer AJCC v8
  • Stage IIB Pancreatic Cancer AJCC v8
  • Stage III Pancreatic Cancer AJCC v8
  • Stage IV Cutaneous Squamous Cell Carcinoma of the Head and Neck AJCC v8
  • Stage IV Lung Cancer AJCC v8
  • Stage IV Pancreatic Cancer AJCC v8
  • Stage IVA Lung Cancer AJCC v8
  • Stage IVB Lung Cancer AJCC v8
  • Unresectable Malignant Solid Neoplasm
  • Unresectable Melanoma
  • Unresectable Pancreatic Adenocarcinoma

Interventions

DrugSynonymsArms
PembrolizumabKeytruda, Lambrolizumab, MK-3475, SCH 900475Treatment (sonidegib, pembrolizumab)
SonidegibErismodegib, LDE-225, LDE225, Odomzo, Smoothened Antagonist LDE225Treatment (sonidegib, pembrolizumab)

Purpose

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.

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 pancreas cancer 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 OBJECTIVES:

      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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (sonidegib, pembrolizumab)ExperimentalPatients 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.
  • Pembrolizumab
  • Sonidegib

Eligibility Criteria

        Inclusion Criteria:

          -  Resolution of adverse events (AEs) from prior treatment to baseline, or Common
             Terminology Criteria for Adverse Events (CTCAE) =< grade 1 unless AEs are clinically
             nonsignificant and/or stable with supportive therapy.

          -  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).

                    -  Tumor expression of PD-L1 (tumor propensity score >= 1%) as determined using
                       an Food and Drug Administration (FDA)-approved test.

                    -  Disease progression on prior platinum-containing chemotherapy.

                         -  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.

               -  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 after progression on 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: Refractory metastatic or inoperable pancreatic
             adenocarcinoma.

               -  Pathologically confirmed metastatic or inoperable pancreatic adenocarcinoma.

               -  Received at least (>=)1 prior line of systemic chemotherapy for advanced or
                  metastatic disease.

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

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

               -  Tumor expression of PD-L1 (tumor propensity score >= 1%) as determined using an
                  FDA-approved test.

               -  Disease progression on >= 2 prior lines of systemic therapy, including prior
                  platinum-containing chemotherapy.

                    -  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
                  or five half-lives, whichever is longer, 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
        14 days or 5 half-lives, whichever is longer, 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 an experimental drug or anti-neoplastic therapy =< 4 weeks prior to
             registration (or 5 half-lives, whichever is longer).

          -  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.

               -  Severe preexisting medical condition, active infection >= grade 2 according to
                  the National Cancer Institute (NCI)-CTCAE version (v)5.0, or co-morbidity that,
                  in the judgment of the investigator, would make the patient inappropriate for
                  this study.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose (MTD) of sonidegib in combination with pembrolizumab (Part A)
Time Frame:Up to 21 days
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:Incidence of adverse events
Time Frame:Up to 30 days post treatment
Safety Issue:
Description: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.
Measure:Response profile
Time Frame:Up to 30 days post treatment
Safety Issue:
Description: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.
Measure: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
Safety Issue:
Description: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.
Measure:Disease control rate (DCR)
Time Frame:At 6 months
Safety Issue:
Description: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.
Measure:Overall survival (OS)
Time Frame:From study entry to death from any cause, assessed up to 30 days post treatment
Safety Issue:
Description:Will be estimated using Kaplan-Meier method.
Measure: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
Safety Issue:
Description:Disease progression will be determined based on RECIST 1.1 criteria. PFS will be estimated using the Kaplan-Meier method.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Mayo Clinic

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