Clinical Trials /

A Phase 1 Study to Investigate SNDX-6352 Alone or in Combination With Durvalumab in Patients With Solid Tumors

NCT03238027

Description:

A Phase 1 dose escalation study to determine if SNDX-6352 as monotherapy and SNDX-6352 in combination with a fixed dose of durvalumab will be sufficiently safe and well-tolerated at biologically active doses to warrant further investigation in patients with solid tumors.

Related Conditions:
  • Malignant Solid Tumor
Recruiting Status:

Active, not recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: A Phase 1 Study to Investigate SNDX-6352 Alone or in Combination With Durvalumab in Patients With Solid Tumors
  • Official Title: Phase 1, Open-Label Dose Escalation Trial to Investigate Safety and Tolerability of SNDX-6352 Monotherapy and SNDX-6352 in Combination With Durvalumab in Patients With Unresectable, Recurrent, Locally-Advanced, or Metastatic Solid Tumors

Clinical Trial IDs

  • ORG STUDY ID: SNDX-6352-0502
  • NCT ID: NCT03238027

Conditions

  • Solid Tumor
  • Metastatic Tumor
  • Locally Advanced Malignant Neoplasm
  • Unresectable Malignant Neoplasm

Interventions

DrugSynonymsArms
SNDX-6352Ph1a D1: 1 mg/kg SNDX-6352
DurvalumabMEDI4736Ph1b D1: 1 mg/kg SNDX-6352+1500mg durva

Purpose

A Phase 1 dose escalation study to determine if SNDX-6352 as monotherapy and SNDX-6352 in combination with a fixed dose of durvalumab will be sufficiently safe and well-tolerated at biologically active doses to warrant further investigation in patients with solid tumors.

Detailed Description

      This is an open label, multi-center Phase 1 study consisting of Phase 1a and Phase 1b. The
      study will evaluate SNDX-6352 monotherapy (in Phase 1a) and SNDX-6352 combined with
      durvalumab (in Phase 1b) in patients with advanced solid tumors which must have progressed
      following prior treatment and have no standard therapy alternatives left (i.e.. patients must
      not be candidates for regimens known to provide clinical benefit). The primary objective will
      be to determine the MTD and/or RP2D of SNDX-6352 as monotherapy (Phase 1a) and in combination
      with durvalumab (Phase 1b) as evaluated by the incidence of AEs that are defined as DLTs. In
      both study phases, a standard "3+3"dose escalation schema will be used to determine an MTD
      with 3-6 evaluable patients enrolled per dose level. The RP2D will be determined based on
      data from the dose escalation patients as reviewed by the Safety Review Committee (SRC;
      comprised of investigators and the Sponsor).
    

Trial Arms

NameTypeDescriptionInterventions
Ph1a D1: 1 mg/kg SNDX-6352ExperimentalThree (3) patients receive starting dose of 1 mg/kg of SNDX-6352 and are followed for possible DLTs. If one DLT is observed in 1 of 3 patients, an additional 3 patients will be enrolled at this dose level. If no DLTs are noted in any of the 3 patients, next dosing arm will commence following review by Scientific Review Committee.
  • SNDX-6352
Ph1a D2: 3 mg/kg SNDX-6352ExperimentalThree (3) patients receive next higher dose of 3 mg/kg of SNDX-6352 and are followed for possible DLTs. If one DLT is observed in 1 of 3 patients, an additional 3 patients will be enrolled at this dose level. If no DLTs are noted in any of the 3 patients, next dosing arm will commence following review by Scientific Review Committee.
  • SNDX-6352
Ph1a D3: 6 mg/kg SNDX-6352ExperimentalThree (3) patients receive next higher dose of 6 mg/kg of SNDX-6352 and are followed for possible DLTs. If one DLT is observed in 1 of 3 patients, an additional 3 patients will be enrolled at this dose level. If no DLTs are noted in any of the 3 patients, next dosing arm will commence following review by Scientific Review Committee.
  • SNDX-6352
Ph1a D4: 10 mg/kg SNDX-6352ExperimentalThree (3) patients receive next higher dose of 10 mg/kg of SNDX-6352 and are followed for possible DLTs. If one DLT is observed in 1 of 3 patients, an additional 3 patients will be enrolled at this dose level. If no DLTs are noted in any of the 3 patients, next dosing arm will commence following review by Scientific Review Committee.
  • SNDX-6352
Ph1b D1: 1 mg/kg SNDX-6352+1500mg durvaExperimentalThree (3) patients receive starting dose of 1 mg/kg of SNDX-6352 every two weeks and 1500mg durvalumab every four weeks and are followed for possible DLTs. If one DLT is observed in 1 of 3 patients, an additional 3 patients will be enrolled at this dose level. If no DLTs are noted in any of the 3 patients, next dosing arm will commence following review by Scientific Review Committee. If 1 DLT is observed in 1 of 3 patients, then 3 additional patients will be treated at the 1 mg/kg SNDX-6352 dose level; if none of the 3 additional patients experience a DLT (i.e. 1 of 6), the dose will be escalated to an intermediate dose of 2 mg/kg. Escalation from 2 mg/kg to 3 mg/kg will follow the general dose escalation rules described above for both study phases.
  • SNDX-6352
  • Durvalumab
Ph1b D2: 3 mg/kg SNDX-6352+1500mg durvaExperimentalThree (3) patients receive next higher dose of 3 mg/kg of SNDX-6352 every two weeks and 1500mg durvalumab every four weeks and are followed for possible DLTs. For cohorts with doses ≥3 mg/kg, a sentinel recruitment approach will be utilized. Initially 1 patient in each cohort will be treated with the combination therapy and safety will be evaluated by SRC at Cycle 1, Day 8; if no safety concerns are identified, the next 2 patients can be treated in that cohort. If one DLT is observed in 1 of 3 patients, an additional 3 patients will be enrolled at this dose level. If no DLTs are noted in any of the 3 patients, next dosing arm will commence following review by Scientific Review Committee.
  • SNDX-6352
  • Durvalumab
Ph1b D3: 3 mg/kg SNDX-6352+1500mg durvaExperimentalThree (3) patients receive next higher dose of 6 mg/kg of SNDX-6352 every two weeks and 1500mg durvalumab every four weeks and are followed for possible DLTs. For cohorts with doses ≥3 mg/kg, a sentinel recruitment approach will be utilized. Initially 1 patient in each cohort will be treated with the combination therapy and safety will be evaluated by SRC at Cycle 1, Day 8; if no safety concerns are identified, the next 2 patients can be treated in that cohort. If one DLT is observed in 1 of 3 patients, an additional 3 patients will be enrolled at this dose level. If no DLTs are noted in any of the 3 patients, next dosing arm will commence following review by Scientific Review Committee.
  • SNDX-6352
  • Durvalumab

Eligibility Criteria

        INCLUSION CRITERIA:

        Inclusion Criteria for Phase 1a and Phase 1b

        Patients meeting all of the following criteria are considered eligible to participate in
        the study:

          1. Signed written informed consent form (ICF).

          2. Male or female patients aged ≥18 years.

          3. Patients with histopathologically confirmed unresectable, recurrent, locally-advanced,
             or metastatic solid tumors, with evaluable disease and must have progressed following
             prior treatment and have no standard therapy alternatives left (ie: patients must not
             be candidates for regimens known to provide clinical benefit).

          4. Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1 at the study
             enrollment.

          5. Has adequate organ and bone marrow function within 21 days before enrollment as
             defined below:

             a. Hematological laboratory values: i. Absolute Neutrophil Count (ANC) ≥1.5 × 109/L
             ii. Platelets ≥100 × 109/L iii. Hemoglobin ≥9 g/dL b. Renal laboratory values: i.
             Creatinine ≤1.5 times the Upper Limit of Normal (ULN) OR ii. Measured or calculated
             (per institutional standard) creatinine clearance (CrCl) ≥60 mL/min according to the
             Cockcroft-Gault formula or measured 24-hour creatinine clearance (or local
             institutional standard measure) for patient with creatinine level > 1.5 times
             institutional ULN.

             iii. Glomerular filtration rate may be used instead of creatinine or CrCl. c. Hepatic
             laboratory values: i. Total bilirubin ≤1.5 times ULN or ii. Direct bilirubin ≤ULN for
             patients with total bilirubin >1.5 times ULN iii. AST and ALT ≤2.5 times ULN d.
             Creatine kinase ≤ ULN

          6. Experienced resolution of toxic effect(s) of the most recent prior anti-cancer therapy
             to Grade ≤1 (except alopecia) per NCI CTCAE v5.0 If a patient underwent major surgery
             or radiation therapy of >30 Gray, the patient must have recovered from the toxicity
             and/or complications from the intervention.

             Note: Patients with ≤ Grade 2 neuropathy or ≤ Grade 2 alopecia are an exception to
             this criterion and may qualify for the study.

          7. Evidence of post-menopausal status or negative urinary or serum pregnancy test for
             female pre-menopausal patients. Women will be considered post-menopausal if they have
             been amenorrheic for 12 months without an alternative medical cause. The following
             age-specific requirements apply:

               -  Women <50 years of age would be considered post-menopausal if they have been
                  amenorrheic for 12 months or more following cessation of exogenous hormonal
                  treatments and if they have luteinizing hormone and follicle-stimulating hormone
                  levels in the post-menopausal range for the institution or underwent surgical
                  sterilization (bilateral oophorectomy or hysterectomy).

               -  Women ≥50 years of age would be considered post-menopausal if they have been
                  amenorrheic for 12 months or more following cessation of all exogenous hormonal
                  treatments, had radiation-induced menopause with last menses >1 year ago, had
                  chemotherapy-induced menopause with last menses >1 year ago, or underwent
                  surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or
                  hysterectomy).

          8. Female patients of childbearing potential who are not abstinent and intend to be
             sexually active with a nonsterilized male partner must use at least 1 highly effective
             method of contraception (Table 11) from the time of screening throughout the total
             duration of the study drug treatment and 90 days after the last dose of study drug.
             Non-sterilized male partners of a female patient of childbearing potential must use
             male condom plus spermicide throughout this period. Cessation of birth control after
             this point should be discussed with a responsible physician. Periodic abstinence, the
             rhythm method, and the withdrawal method are not acceptable methods of birth control.
             Female patients should also refrain from breastfeeding throughout this period.

          9. Non-sterilized male patients who are not abstinent and intend to be sexually active
             with a female partner of childbearing potential must use a male condom plus spermicide
             from the time of screening throughout the total duration of the study drug treatment
             and 90 days after the last dose of study drug. However, periodic abstinence, the
             rhythm method, and the withdrawal method are not acceptable methods of contraception.
             Male patients should refrain from sperm donation throughout this period.

         10. Must have a life expectancy of at least 12 weeks.

        Additional Inclusion Criteria for Phase 1b 11. Body weight > 30 kg 12. No prior exposure to
        immune-mediated therapy including, but not limited to, other anti CTLA-4, anti-PD-1,
        anti-PD-L1, and anti-PD-L2 antibodies, excluding therapeutic anticancer vaccines.

        EXCLUSION CRITERIA:

        Exclusion Criteria for Phase 1a and Phase 1b

        Patients meeting any of the following criteria are not eligible for study participation:

          1. Diagnosis of immunodeficiency or receiving systemic corticosteroid therapy or any
             other form of immunosuppressive therapy within 14 days prior to the first dose of
             study drug.

             a. Exceptions: 1) The use of physiologic doses of corticosteroids (i.e., ≤10 mg per
             day of equivalent prednisone) is allowed; 2) Steroids with no or minimal systemic
             effect (topical, inhalation) are allowed; 3) Replacement therapy (e.g., thyroxine,
             insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary
             insufficiency) is not considered a form of systemic treatment; (4) Steroids as
             premedication for hypersensitivity reactions (e.g., CT scan premedication).

          2. Previously treated with a CSF-1, CSF-1R, and/or IL-34-blocking agents

          3. Psychiatric illness/social situations that would limit compliance with study
             requirement, substantially increase risk of incurring AEs or compromise the ability of
             the patient to give written informed consent

          4. History or current evidence of any condition, therapy, or laboratory abnormality that
             might confound the results of the study, interfere with the patient's participation
             for the full duration of the study, or is not in the patient's best interest to
             participate, in the opinion of the treating Investigator, including, but not limited
             to:

               1. Active or prior documented autoimmune or inflammatory disorders (see Appendix 3
                  for complete list).

               2. History of active primary immunodeficiency

               3. Known active or latent tuberculosis (clinical evaluation that includes clinical
                  history, physical examination and radiographic findings, and tuberculosis testing
                  in line with local practice).

               4. Myocardial infarction or arterial thromboembolic events within 6 months prior to
                  enrollment or severe or unstable angina, New York Heart Association (NYHA) (see
                  Appendix 2) Class III or IV disease, or a QTc interval > 470 msec. History of QTc
                  prolongation, ventricular fibrillation, ventricular tachycardia or Torsades de
                  Pointes (TdP).

               5. Symptomatic congestive heart failure, cardiac arrhythmia, uncontrolled
                  hypertension or diabetes mellitus.

               6. Active infection requiring systemic therapy.

               7. Interstitial lung disease

               8. Serious chronic gastrointestinal conditions associated with diarrhea

               9. Has untreated central nervous system (CNS) metastases and/or carcinomatous
                  meningitis identified either on the baseline brain imaging (please see Appendix A
                  (RECIST)) for details on the imaging modality) obtained during the screening
                  period or identified prior to signing the ICF. Patients whose brain metastases
                  have been treated may participate provided they show radiographic stability
                  (defined as 2 brain images, both of which are obtained after treatment to the
                  brain metastases. These imaging scans should both be obtained at least four weeks
                  apart and show no evidence of intracranial progression). In addition, any
                  neurologic symptoms that developed either as a result of the brain metastases or
                  their treatment must have resolved or be stable either, without the use of
                  steroids, or are stable on a steroid dose of ≤10 mg/day of prednisone or its
                  equivalent for at least 14 days prior to the start of treatment. Brain metastases
                  will not be recorded as RECIST Target Lesions at baseline.

          5. Received a live attenuated vaccine within 30 days of the first dose of study drug.

             Note: Patients, if enrolled, should not receive live vaccine whilst receiving study
             drug and up to 30 days after the last dose of study drug.

          6. Administration of colony stimulating factors (including granulocyte-colony stimulating
             factor [G-CSF], granulocyte macrophage-colony stimulating factor [GM-CSF], or
             recombinant erythropoietin) within 4 weeks prior to the first dose of study drug
             treatment.

          7. Concurrent enrolment in another clinical study, unless it is an observational
             (non-interventional) clinical study or during the follow-up period of an
             interventional study

          8. Received chemotherapy, anti-cancer mAb, targeted small molecule or other systemic
             anti-cancer therapy within 4 weeks of the first dose of study drug. However, patients
             receiving conventional and investigational small molecule targeted therapies that are
             not expected to have delayed toxicities may enter the study 5 half-lives or 28 days
             after the last dose of the compound, whichever is shorter.

          9. Currently receiving treatment with any other agent listed on the prohibited medication
             list (see Section 7.11).

         10. Known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies).

         11. Known active hepatitis B (e.g., hepatitis B surface antigen-reactive) or hepatitis C
             (e.g., hepatitis C virus ribonucleic acid [qualitative]). Patients with past hepatitis
             B virus (HBV) infection or resolved HBV infection (defined as the presence of
             hepatitis B core antibody [HBc Ab] and absence of HBsAg) are eligible. Patients
             positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain
             reaction is negative for HCV RNA.

         12. Known alcohol or drug abuse.

         13. Known psychiatric or substance abuse disorders that would interfere with cooperation
             with the requirements of the study.

         14. Legal incapacity or limited legal capacity.

         15. Evidence of muscle disorders or muscle injury that are known to cause serum creatine
             kinase (CK) elevation

         16. Current pneumonitis or has a history of (non-infectious) pneumonitis that required
             steroids

         17. Known allergy or hypersensitivity to any of the study drugs or any of the study drug
             excipients.

         18. Major surgical procedure (as defined by the Investigator) within 28 days prior to the
             first dose of study drug. Note: Local surgery of isolated lesions for palliative
             intent is acceptable.

         19. Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of
             radiation within 4 weeks or palliative radiation therapy within 2 weeks of the first
             dose of study drug

         20. Female patients who are pregnant or breastfeeding or male or female patients of
             reproductive potential who are not willing to employ effective birth control from
             screening to 90 days after the last dose of study drug

             Additional Exclusion Criteria for Phase 1b

         21. History of allogenic organ transplantation.

         22. Patients who have received prior anti-PD-1, anti PD-L1 or anti CTLA-4.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Phase 1a: Determination of any Dose limiting toxicities (DLT)s of SNDX-6352
Time Frame:Approximately 9 months (from first dose to 90-day follow-up post-last dose)
Safety Issue:
Description:All patients treated with SNDX-6352 across all treatment arms (dosing levels) will have safety assessed in order to determine any dose-limiting toxicities (DLT)s.

Secondary Outcome Measures

Measure:Phase 1a: PK endpoint of Cmax (maximum observed concentration) for SNDX-6352 as dose levels increase across different treatment groups.
Time Frame:Approximately 6 months (from first dose to End of Treatment visit)
Safety Issue:
Description:Cmax for SDNX-6352 for SNDX-6352 will be computed.
Measure:Phase 1a: PK endpoint of AUC (area under the curve) for SNDX-6352 as dose levels increase across different treatment groups.
Time Frame:Approximately 6 months (from first dose to End of Treatment visit)
Safety Issue:
Description:AUC for SDNX-6352 for SNDX-6352 will be computed.
Measure:Phase 1a: PK endpoint of Tmax (time to reach maximum observed concentration) for SNDX-6352 as dose levels increase across different treatment groups.
Time Frame:Approximately 6 months (from first dose to End of Treatment visit)
Safety Issue:
Description:Tmax for SDNX-6352 for SNDX-6352 will be computed.
Measure:Phase 1a: PK endpoint of T1/2 (apparent terminal elimination half life)) for SNDX-6352 as dose levels increase across different treatment groups.
Time Frame:Approximately 6 months (from first dose to End of Treatment visit)
Safety Issue:
Description:T1/2 for SDNX-6352 for SNDX-6352 will be computed.
Measure:Phase 1a: Evaluation of preliminary anti-tumor activity of SNDX-6352 on solid tumors
Time Frame:Approximately 9 months (from baseline scan to 90-day follow-up post-last dose)
Safety Issue:
Description:To determine if the size and number of target lesions changes in response to treatment with SNDX-6352 by analyzing CT-Scans/MRIs per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) and irRECIST.
Measure:Phase 1a: Effect of SNDX-6352 on CSF-1 and IL-34
Time Frame:Approximately 6 months (from first dose to End of Treatment visit)
Safety Issue:
Description:To assess change from Baseline in plasma CSF-1 and IL-34 following IV administration
Measure:Phase 1a: Evaluate the immunogenicity of SNDX-6352
Time Frame:Approximately 6 months (from first dose to End of Treatment visit)
Safety Issue:
Description:To assess the immunogenicity of SNDX-6352 as measured by presence of anti-drug antibodies (ADA)
Measure:Phase 1b: PK endpoint of Cmax (maximum observed concentration) for SNDX-6352 when given in combination with a fixed dose of durvalumab as dose levels increase across different treatment groups.
Time Frame:Approximately 6 months (from first dose to End of Treatment visit)
Safety Issue:
Description:Cmax for SNDX-6352 will be computed.
Measure:Phase 1b: PK endpoint of AUC (area under the curve) for SNDX-6352 when given in combination with a fixed dose of durvalumab as dose levels increase across different treatment groups.
Time Frame:Approximately 6 months (from first dose to End of Treatment visit)
Safety Issue:
Description:AUC for SNDX-6352 will be computed.
Measure:Phase 1b: PK endpoint of Tmax (time to reach maximum observed concentration) for SNDX-6352 when given in combination with a fixed dose of durvalumab as dose levels increase across different treatment groups.
Time Frame:Approximately 6 months (from first dose to End of Treatment visit)
Safety Issue:
Description:Tmax for SNDX-6352 will be computed.
Measure:Phase 1b: PK endpoint of T1/2 (apparent terminal elimination half-life)) for SNDX-6352 when given in combination with a fixed dose of durvalumab as dose levels increase across different treatment groups.
Time Frame:Approximately 6 months (from first dose to End of Treatment visit)
Safety Issue:
Description:T1/2 for SNDX-6352 will be computed.
Measure:Phase 1b: PK endpoint of Cmax (maximum observed concentration) for durvalumab when given in combination with SNDX-6352 as dose levels increase across different treatment groups.
Time Frame:Approximately 6 months (from first dose to End of Treatment visit)
Safety Issue:
Description:Cmax for durvalumab will be computed.
Measure:Phase 1b: PK endpoint of AUC (area under the curve) for durvalumab when given in combination with SNDX-6352 as dose levels increase across different treatment groups.
Time Frame:Approximately 6 months (from first dose to End of Treatment visit)
Safety Issue:
Description:AUC for durvalumab will be computed.
Measure:Phase 1b: PK endpoint of Tmax (time to reach maximum observed concentration) for durvalumab when given in combination with SNDX-6352 as dose levels increase across different treatment groups.
Time Frame:Approximately 6 months (from first dose to End of Treatment visit)
Safety Issue:
Description:Tmax for durvalumab will be computed.
Measure:Phase 1b: PK endpoint of T1/2 (apparent terminal elimination half-life) for durvalumab when given in combination with SNDX-6352 as dose levels increase across different treatment groups.
Time Frame:Approximately 6 months (from first dose to End of Treatment visit)
Safety Issue:
Description:T1/2 for durvalumab will be computed.
Measure:Phase 1b: Evaluation of preliminary anti-tumor activity of SNDX-6352 when given in combination with a fixed dose of durvalumab on solid tumors.
Time Frame:Approximately 9 months (from baseline scan to 90-day follow-up post-last dose)
Safety Issue:
Description:To determine if the size and number of target lesions changes in response to treatment with SNDX-6352 by analyzing CT-Scans/MRIs per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) and irRECIST.
Measure:Phase 1b: Effect of SNDX-6352 on CSF-1 and IL-34
Time Frame:Approximately 6 months (from first dose to End of Treatment visit)
Safety Issue:
Description:To assess change from Baseline in plasma CSF-1 and IL-34 following IV administration
Measure:Phase 1b: Evaluation of the immunogenicity of SNDX-6352
Time Frame:Approximately 6 months (from first dose to End of Treatment visit)
Safety Issue:
Description:To assess the immunogenicity of SNDX-6352 as measured by presence of anti-drug antibodies (ADA)
Measure:Phase 1b: Evaluation of the immunogenicity of durvalumab
Time Frame:Approximately 6 months (from first dose to End of Treatment visit)
Safety Issue:
Description:To assess the immunogenicity of durvalumab as measured by presence of anti-drug antibodies (ADA)

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Syndax Pharmaceuticals

Trial Keywords

  • SNDX-6352
  • CSF-1R inhibitor
  • Colony Stimulating factor 1 receptor inhibitor
  • Solid Tumor
  • Recurrent locally advanced tumor
  • unresectable solid tumor
  • Metastatic tumor
  • durvalumab

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