A Phase 1 Study to Investigate Axatilimab Alone or in Combination With Durvalumab in Patients With Solid Tumors

NCT03238027 | Completed Phase 1 DMC FDA Drug

• 1 other identifier: SNDX-6352-0502
• Study Type: interventional
• Target: 45
• Locations: 1 country
• Sites: 5

Brief Summary

A Phase 1 dose escalation study to determine if axatilimab as monotherapy and axatilimab 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.

Conditions

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

Keywords

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

Outcome Measures

Primary Outcomes (6)

• Phase 1a: Determination of any Dose limiting toxicities (DLT)s of Axatilimab

  All patients treated with axatilimab across all treatment arms (dosing levels) will have safety assessed in order to determine any dose-limiting toxicities (DLT)s.

  Approximately 9 months (from first dose to 90-day follow-up post-last dose)

• Phase 1a: Determination of Maximum tolerable dose (MTD) of Axatilimab

  All patients treated with axatilimab across all treatment arms (dosing levels) will have safety assessed in order to determine the MTD.

  Approximately 9 months (from first dose to 90-day follow-up post-last dose)

• Phase 1a: Determination of Recommended Phase 2 dose (RP2D) of Axatilimab

  All patients treated with axatilimab across all treatment arms (dosing levels) will have safety assessed in order to determine the RP2D.

  Approximately 9 months (from first dose to 90-day follow-up post-last dose)

• Phase 1b: Determination of any Dose limiting toxicities (DLT)s of Axatilimab when given in combination with a fixed dose of durvalumab

  All patients treated with axatilimab in combination with a fixed dose of durvalumab across all treatment arms (dosing levels) will have safety assessed in order to determine any dose-limiting toxicities (DLT)s.

  Approximately 9 months (from first dose to 90-day follow-up post-last dose)

• Phase 1b: Determination of Maximum tolerable dose (MTD) of Axatilimab when given in combination with a fixed dose of durvalumab

  All patients treated with axatilimab in combination with a fixed dose of durvalumab across all treatment arms (dosing levels) will have safety assessed in order to determine the MTD.

  Approximately 9 months (from first dose to 90-day follow-up post-last dose)

• Phase 1b: Determination of Recommended Phase 2 dose (RP2D) of Axatilimab when given in combination with a fixed dose of durvalumab

  All patients treated with axatilimab in combination with a fixed dose of durvalumab across all treatment arms (dosing levels) will have safety assessed in order to determine the RP2D.

  Approximately 9 months (from first dose to 90-day follow-up post-last dose)

Secondary Outcomes (19)

• Phase 1a: PK endpoint of Cmax (maximum observed concentration) for Axatilimab as dose levels increase across different treatment groups.

  Approximately 6 months (from first dose to End of Treatment visit)

• Phase 1a: PK endpoint of AUC (area under the curve) for Axatilimab as dose levels increase across different treatment groups.

  Approximately 6 months (from first dose to End of Treatment visit)

• Phase 1a: PK endpoint of Tmax (time to reach maximum observed concentration) for Axatilimab as dose levels increase across different treatment groups.

  Approximately 6 months (from first dose to End of Treatment visit)

• Phase 1a: PK endpoint of T1/2 (apparent terminal elimination half life)) for Axatilimab as dose levels increase across different treatment groups.

  Approximately 6 months (from first dose to End of Treatment visit)

• Phase 1a: Evaluation of preliminary anti-tumor activity of Axatilimab on solid tumors

  Approximately 9 months (from baseline scan to 90-day follow-up post-last dose)

Other Outcomes (9)

• Phase 1a: Effect of Axatilimab on CSF-1 receptor occupancy

  Approximately 6 months (from first dose to End of Treatment visit)

• Phase 1a: Exploration of relationship between candidate biomarker results and anti-tumor activity of Axatilimab

  Approximately 6 months (from first dose to End of Treatment visit)

• Phase 1a: Exploration of relationship between additional biomarkers and anti-tumor activity of Axatilimab

  Approximately 6 months (from first dose to End of Treatment visit)

Study Arms (7)

Ph1a D1: 1 mg/kg Axatilimab

EXPERIMENTAL

Three (3) patients receive starting dose of 1 mg/kg of axatilimab 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: Axatilimab

Ph1a D2: 3 mg/kg Axatilimab

EXPERIMENTAL

Three (3) patients receive next higher dose of 3 mg/kg of axatilimab 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: Axatilimab

Ph1a D3: 6 mg/kg Axatilimab

EXPERIMENTAL

Three (3) patients receive next higher dose of 6 mg/kg of axatilimab 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: Axatilimab

Ph1a D4: 10 mg/kg Axatilimab

EXPERIMENTAL

Three (3) patients receive next higher dose of 10 mg/kg of axatilimab 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: Axatilimab

Ph1b D1: 1 mg/kg Axatilimab+1500 mg durvalumab

EXPERIMENTAL

Three (3) patients receive starting dose of 1 mg/kg of axatilimab every two weeks and 1500 mg 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 axatilimab 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.

Drug: Axatilimab; Drug: Durvalumab

Ph1b D2: 3 mg/kg Axatilimab+1500 mg durvalumab

EXPERIMENTAL

Three (3) patients receive next higher dose of 3 mg/kg of axatilimab every two weeks and 1500 mg 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.

Drug: Axatilimab; Drug: Durvalumab

Ph1b D3: 6 mg/kg Axatilimab+1500 mg durvalumab

EXPERIMENTAL

Three (3) patients receive next higher dose of 6 mg/kg of axatilimab every two weeks and 1500 mg 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.

Drug: Axatilimab; Drug: Durvalumab

Interventions

Axatilimab DRUG

Humanized IgG4 mAb that blocks colony stimulating factor 1 receptor (CSF-1R)

Also known as: SNDX-6352

Ph1a D1: 1 mg/kg Axatilimab; Ph1a D2: 3 mg/kg Axatilimab; Ph1a D3: 6 mg/kg Axatilimab; Ph1a D4: 10 mg/kg Axatilimab; Ph1b D1: 1 mg/kg Axatilimab+1500 mg durvalumab; Ph1b D2: 3 mg/kg Axatilimab+1500 mg durvalumab; Ph1b D3: 6 mg/kg Axatilimab+1500 mg durvalumab

Durvalumab DRUG

Durvalumab (MEDI4736) is a humanized IgG1 kappa mAb that blocks the interaction of PD-L1 with PD-1 CD80 (B7.1) molecules

Also known as: MEDI4736

Ph1b D1: 1 mg/kg Axatilimab+1500 mg durvalumab; Ph1b D2: 3 mg/kg Axatilimab+1500 mg durvalumab; Ph1b D3: 6 mg/kg Axatilimab+1500 mg durvalumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients meeting all of the following criteria are considered eligible to participate in the study:
• Signed written informed consent form (ICF).
• Male or female patients aged ≥18 years.
• 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 (i.e., patients must not be candidates for regimens known to provide clinical benefit).
• Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1 at the study enrollment.
• 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 × 10\^9/L ii. Platelets ≥100 × 10\^9/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
• 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.
• 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).
• 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.
• 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.

You may not qualify if:

• Patients meeting any of the following criteria are not eligible for study participation:
• 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).
• Previously treated with a CSF-1, CSF-1R, and/or IL-34-blocking agents
• 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
• 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:
• Active or prior documented autoimmune or inflammatory disorders (see Appendix 3 for complete list).
• History of active primary immunodeficiency
• Known active or latent tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and tuberculosis testing in line with local practice).
• 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).
• Symptomatic congestive heart failure, cardiac arrhythmia, uncontrolled hypertension or diabetes mellitus.
• Active infection requiring systemic therapy.
• Interstitial lung disease
• Serious chronic gastrointestinal conditions associated with diarrhea
• 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.

Sponsors & Collaborators

• Syndax Pharmaceuticals: lead

Study Sites (5)

Honor Health

Scottsdale, Arizona, 85258, United States

Location

Johns Hopkins University

Baltimore, Maryland, 21287, United States

Location

Oregon Health and Science University

Portland, Oregon, 97239, United States

Location

NEXT Oncology

San Antonio, Texas, 78229, United States

Location

South Texas Accelerated Research Therapeutics

San Antonio, Texas, 78229, United States

Location

MeSH Terms

Conditions

Neoplasm Metastasis

Interventions

axatilimab; durvalumab

Condition Hierarchy (Ancestors)

Neoplastic Processes; Neoplasms; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Kate Madigan, MD

  Syndax Pharmaceuticals

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Initially in both phases, 3 patients will receive axatilimab at 1 mg/kg IV on C1D1 and again on C1D15 of a 28-day cycle. Phase 1b only will also receive a fixed dose of 1500mg durvalumab IV on C1D1. If no DLTs are noted, 3 more patients will be treated at the next higher dose level (3 mg/kg). If 1 DLT is observed in 1 of 3 patients, 3 more 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. If the safety profile is acceptable, escalation to axatilimab doses of 3, 6 and 10mg/kg are planned for the 1a and for the 1b, doses of 3 and 6 mg/kg of axatilimab in combination with a fixed dose of 1500mg of durvalumab are 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.

Study Record Dates

• First Submitted: June 30, 2017
• First Posted: August 3, 2017
• Study Start: September 1, 2017
• Primary Completion: November 20, 2020
• Study Completion: November 20, 2020
• Last Updated: May 17, 2024

Record last verified: 2024-05

Data Sharing

• IPD Sharing: Will not share

Locations

US (5)