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A Phase 1, Open-label, Dose Escalation Trial to Investigate SNDX-6352 in Patients With Solid Tumors

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ClinicalTrials.gov Identifier: NCT03238027
Recruitment Status : Recruiting
First Posted : August 3, 2017
Last Update Posted : January 12, 2018
Sponsor:
Information provided by (Responsible Party):
Syndax Pharmaceuticals

Brief Summary:
A Phase 1 dose escalation study to determine if SNDX-6352 will be sufficiently safe and well-tolerated at biologically active doses to warrant further investigation in patients with solid tumors.

Condition or disease Intervention/treatment Phase
Solid Tumor Metastatic Tumor Locally Advanced Malignant Neoplasm Unresectable Malignant Neoplasm Drug: SNDX-6352 Phase 1

Detailed Description:
This is an open label, multi-center Phase 1 study to evaluate SNDX-6352 in patients with unresectable, recurrent, locally-advanced or metastatic solid tumors which 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). The primary objective will be to determine the safety and maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of SNDX-6352 as evaluated by the incidence of adverse events that are defined as dose-limiting toxicities (DLTs). A standard "3+3" dose escalation schema will be used to determine an MTD with 3-6 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).

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 24 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention Model Description: Initially, 3 patients will receive SNDX-6352 at a starting dose of 1 mg/kg IV on C1D1 and then again on C1D15 of a 28-day cycle. If no DLTs are noted, then 3 more patients will be treated at the next higher dose level (3 mg/kg). If one DLT is observed in 1 of 3 patients, 3 additional patients will be treated at that starting dose level (1 mg/kg). If 2 or more DLTs are observed in 3-6 patients at the starting dose, the study will be terminated or a lower dose will be considered. An SRC will approve dose escalation after the safety assessments for each dose group are completed. If the safety profile is acceptable, escalation to SNDX-6352 doses of 3 mg/kg, 6 mg/kg and 10mg/kg is planned. The MTD will be considered to have been exceeded if 2 or more patients in a dose group experience a DLT; in this case, the next lower dose group which has been evaluated will be considered as the MTD.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1, Open-label, Dose Escalation Trial to Investigate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamic Activity of SNDX-6352 in Patients With Unresectable, Recurrent, Locally-advanced, or Metastatic Solid Tumors
Actual Study Start Date : September 1, 2017
Estimated Primary Completion Date : May 2018
Estimated Study Completion Date : July 2018

Arm Intervention/treatment
Experimental: Dose Level 1: 1 mg/kg SNDX-6352
Three (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.
Drug: SNDX-6352
Humanized IgG4 mAb that blocks colony stimulating factor 1 receptor (CSF-1R)

Experimental: Dose Level 2: 3 mg/kg SNDX-6352
Three (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.
Drug: SNDX-6352
Humanized IgG4 mAb that blocks colony stimulating factor 1 receptor (CSF-1R)

Experimental: Dose Level 3: 6 mg/kg SNDX-6352
Three (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.
Drug: SNDX-6352
Humanized IgG4 mAb that blocks colony stimulating factor 1 receptor (CSF-1R)

Experimental: Dose Level 4: 10 mg/kg SNDX-6352
Three (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.
Drug: SNDX-6352
Humanized IgG4 mAb that blocks colony stimulating factor 1 receptor (CSF-1R)




Primary Outcome Measures :
  1. 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) ]
    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.

  2. Determination of Maximum tolerable dose (MTD) of SNDX-6352 [ Time Frame: Approximately 9 months (from first dose to 90-day follow-up post-last dose) ]
    All patients treated with SNDX-6352 across all treatment arms (dosing levels) will have safety assessed in order to determine the MTD.

  3. Determination of Recommended Phase 2 dose (RP2D) of SNDX-6352 [ Time Frame: Approximately 9 months (from first dose to 90-day follow-up post-last dose) ]
    All patients treated with SNDX-6352 across all treatment arms (dosing levels) will have safety assessed in order to determine the RP2D.


Secondary Outcome Measures :
  1. 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) ]
    Cmax for SDNX-6352 for SNDX-6352 will be computed.

  2. 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) ]
    AUC for SDNX-6352 for SNDX-6352 will be computed.

  3. 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) ]
    Tmax for SDNX-6352 for SNDX-6352 will be computed.

  4. 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) ]
    T1/2 for SDNX-6352 for SNDX-6352 will be computed.

  5. 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) ]
    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.

  6. Effect of SNDX-6352 on CSF-1 and IL-34 [ Time Frame: Approximately 6 months (from first dose to End of Treatment visit) ]
    To assess change from Baseline in plasma CSF-1 and IL-34 following IV administration

  7. Evaluate the immunogenicity of SNDX-6352 [ Time Frame: Approximately 6 months (from first dose to End of Treatment visit) ]
    To assess the immunogenicity of SNDX-6352 as measured by presence of anti-drug antibodies (ADA)


Other Outcome Measures:
  1. Effect of SNDX-6352 on CSF-1 receptor occupancy [ Time Frame: Approximately 6 months (from first dose to End of Treatment visit) ]
    To evaluate the change from Baseline in CSF-1 receptor occupancy (RO)

  2. Exploration of relationship between candidate biomarker results and anti-tumor activity of SNDX-6352 [ Time Frame: Approximately 6 months (from first dose to End of Treatment visit) ]
    To investigate the relationship between candidate biomarkers (e.g., CSF-1, IL-34) and anti-tumor activity of SNDX-6352

  3. Exploration of relationship between additional biomarkers and anti-tumor activity of SNDX-6352 [ Time Frame: Approximately 6 months (from first dose to End of Treatment visit) ]
    To investigate the relationship between other biomarkers (e.g., tumor infiltrating lymphocytes, PD-L1, PD-1, PD-L2, circulating classical and non-classical CD-16 monocytes in blood) and anti-tumor activity of SNDX-6352



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Signed written informed consent
  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 study enrollment
  5. Has adequate organ and bone marrow function within 21 days before enrollment as defined below:

    a. Hematological lab values: i. Absolute Neutrophil Count (ANC) ≥ 1.5 × 109/L ii. Platelets ≥100 × 109/L iii. Hemoglobin ≥9 g/dL (may have been transfused) b. Renal lab 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 lab 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 ≤3 times ULN

  6. Experienced resolution of toxic effect(s) of the most recent prior anticancer therapy to Grade ≤1 (except alopecia), per NCI CTCAE v.4.0. If a patient underwent major surgery or radiation therapy of >30 Gy, the patient must have recovered from the toxicity and/or complications from the intervention.
  7. At Screening, females must be non-pregnant and non-lactating, or of non childbearing potential (either surgically sterilized or physiologically incapable of becoming pregnant, or at least 1 year post menopausal [amenorrhea duration of 12 consecutive months]); pregnancy status will be confirmed by a serum pregnancy test conducted at Screening and a urine pregnancy test before each administration of study drug.
  8. Female patients of child-bearing potential, with a fertile male sexual partner, should be willing to use adequate contraception from 14 days before planned first admission to the clinical research center until 90 days after the last dose of SNDX-6352. Adequate contraception is defined as using hormonal contraceptives or an intrauterine device combined with at least 1 of the following forms of contraception: a diaphragm or cervical cap, or a condom. Total abstinence, in accordance with the patient's lifestyle, is acceptable.
  9. Male patients, if not surgically sterilized, should be willing to use adequate contraception and not donate sperm from first admission to the clinical research center until 90 days after the last follow-up visit. Adequate contraception for the male patient (and his female partner) is defined as using hormonal contraceptives or an intrauterine device combined with at least 1 of the following forms of contraception: a diaphragm or cervical cap, or a condom. Total abstinence, in accordance with the patient's lifestyle, is acceptable.

Exclusion Criteria:

  1. Diagnosis of immunodeficiency or receiving systemic steroid 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., ≤10mg 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.

  2. Previously treated with a CSF-1, CSF-1R, and/or IL-34-blocking agents.
  3. 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. History of immune deficiencies or autoimmune disease (see Appendix 3, Table 12 for complete list).
    2. Known active or latent tuberculosis.
    3. 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).
    4. Uncontrolled hypertension or diabetes mellitus.
    5. Active infection requiring systemic therapy.
    6. Known symptomatic brain metastases requiring steroids. Patients with previously diagnosed brain metastases are eligible if they have completed treatment and have recovered from the acute effects of radiation therapy or surgery prior to study entry, have discontinued corticosteroid treatment for these metastases for at least 4 weeks prior to study entry (exceptions: see exclusion criterion 1) and are neurologically stable (e.g., without seizures). Patients with a history of carcinomatous meningitis are not eligible.
  4. Received a live vaccine within 30 days of the first dose of treatment.
  5. 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.
  6. Currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy within 4 weeks of the first dose of study drug.
  7. Currently receiving treatment with any other agent listed on the prohibited medication list (Section 7.9).
  8. Known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies).
  9. 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.
  10. Kidney and/or liver impairment.
  11. Known alcohol or drug abuse.
  12. Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study.
  13. Legal incapacity or limited legal capacity.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03238027


Contacts
Contact: Anthony J Piscitelli, DC 781-795-9426 ext 438 apiscitelli@syndax.com
Contact: Sue Fischer 781-795-9419 sfischer@syndax.com

Locations
United States, Maryland
Johns Hopkins University Not yet recruiting
Baltimore, Maryland, United States, 21287
Contact: Nilofer Azad, MD       Nazad2@jhmi.edu   
United States, Texas
South Texas Accelerated Research Therapeutics Recruiting
San Antonio, Texas, United States, 78229
Contact: Anthony W Tolcher, MD       Anthony.Tolcher@startsa.com   
Sponsors and Collaborators
Syndax Pharmaceuticals
Investigators
Study Director: Michael L Meyers, MD, PhD Syndax Pharmaceuticals, Inc.

Responsible Party: Syndax Pharmaceuticals
ClinicalTrials.gov Identifier: NCT03238027     History of Changes
Other Study ID Numbers: SNDX-6352-0502
First Posted: August 3, 2017    Key Record Dates
Last Update Posted: January 12, 2018
Last Verified: January 2018
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

Keywords provided by Syndax Pharmaceuticals:
SNDX-6352
CSF-1R inhibitor
Colony Stimulating factor 1 receptor inhibitor
Solid Tumor
Recurrent locally advanced tumor
unresectable solid tumor
Metastatic tumor

Additional relevant MeSH terms:
Neoplasms
Neoplasm Metastasis
Neoplastic Processes
Pathologic Processes