Locally Advanced Malignant Neoplasm, Metastatic Tumor, Solid Tumor, Unresectable Malignant Neoplasm
Conditions
Keywords
SNDX-6352, CSF-1R inhibitor, Colony Stimulating factor 1 receptor inhibitor, Solid Tumor, Recurrent locally advanced tumor, unresectable solid tumor, Metastatic tumor, durvalumab
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.
Detailed description
This is an open label, multi-center Phase 1 study consisting of Phase 1a and Phase 1b. The study will evaluate axatilimab monotherapy (in Phase 1a) and axatilimab 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 axatilimab 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).
Interventions
DRUGAxatilimab
Humanized IgG4 mAb that blocks colony stimulating factor 1 receptor (CSF-1R)
DRUGDurvalumab
Durvalumab (MEDI4736) is a humanized IgG1 kappa mAb that blocks the interaction of PD-L1 with PD-1 CD80 (B7.1) molecules
Sponsors
Syndax Pharmaceuticals
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
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.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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 (i.e., 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 × 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 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1a: Determination of any Dose limiting toxicities (DLT)s of Axatilimab | Approximately 9 months (from first dose to 90-day follow-up post-last dose) | 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. |
| Phase 1b: Determination of Recommended Phase 2 dose (RP2D) of Axatilimab when given in combination with a fixed dose of durvalumab | Approximately 9 months (from first dose to 90-day follow-up post-last dose) | 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. |
| Phase 1b: Determination of Maximum tolerable dose (MTD) of Axatilimab when given in combination with a fixed dose of durvalumab | Approximately 9 months (from first dose to 90-day follow-up post-last dose) | 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. |
| Phase 1b: Determination of any Dose limiting toxicities (DLT)s of Axatilimab when given in combination with a fixed dose of durvalumab | Approximately 9 months (from first dose to 90-day follow-up post-last dose) | 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. |
| Phase 1a: Determination of Recommended Phase 2 dose (RP2D) of Axatilimab | Approximately 9 months (from first dose to 90-day follow-up post-last dose) | All patients treated with axatilimab across all treatment arms (dosing levels) will have safety assessed in order to determine the RP2D. |
| Phase 1a: Determination of Maximum tolerable dose (MTD) of Axatilimab | Approximately 9 months (from first dose to 90-day follow-up post-last dose) | All patients treated with axatilimab across all treatment arms (dosing levels) will have safety assessed in order to determine the MTD. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1b: PK endpoint of AUC (area under the curve) for Axatilimab when given in combination with a fixed dose of durvalumab as dose levels increase across different treatment groups. | Approximately 6 months (from first dose to End of Treatment visit) | AUC for axatilimab will be computed. |
| Phase 1b: PK endpoint of T1/2 (apparent terminal elimination half-life)) for Axatilimab when given in combination with a fixed dose of durvalumab as dose levels increase across different treatment groups. | Approximately 6 months (from first dose to End of Treatment visit) | T1/2 for axatilimab will be computed. |
| Phase 1b: PK endpoint of Cmax (maximum observed concentration) for durvalumab when given in combination with Axatilimab as dose levels increase across different treatment groups. | Approximately 6 months (from first dose to End of Treatment visit) | Cmax for durvalumab will be computed. |
| Phase 1b: PK endpoint of AUC (area under the curve) for durvalumab when given in combination with Axatilimab as dose levels increase across different treatment groups. | Approximately 6 months (from first dose to End of Treatment visit) | AUC for durvalumab will be computed. |
| Phase 1b: PK endpoint of Tmax (time to reach maximum observed concentration) for durvalumab when given in combination with Axatilimab as dose levels increase across different treatment groups. | Approximately 6 months (from first dose to End of Treatment visit) | Tmax for durvalumab will be computed. |
| Phase 1b: PK endpoint of T1/2 (apparent terminal elimination half-life) for durvalumab when given in combination with Axatilimab as dose levels increase across different treatment groups. | Approximately 6 months (from first dose to End of Treatment visit) | T1/2 for durvalumab will be computed. |
| Phase 1b: Evaluation of preliminary anti-tumor activity of Axatilimab when given in combination with a fixed dose of durvalumab on solid tumors. | 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 axatilimab by analyzing CT-Scans/MRIs per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) and irRECIST. |
| Phase 1b: Effect of Axatilimab on CSF-1 and IL-34 | 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 |
| Phase 1b: Evaluation of the immunogenicity of Axatilimab | Approximately 6 months (from first dose to End of Treatment visit) | To assess the immunogenicity of axatilimab as measured by presence of anti-drug antibodies (ADA) |
| Phase 1b: Evaluation of the immunogenicity of durvalumab | Approximately 6 months (from first dose to End of Treatment visit) | To assess the immunogenicity of durvalumab as measured by presence of anti-drug antibodies (ADA) |
| 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) | Cmax for SDNX-6352 for axatilimab will be computed. |
| 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) | AUC for SDNX-6352 for axatilimab will be computed. |
| 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) | Tmax for SDNX-6352 for axatilimab will be computed. |
| 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) | T1/2 for SDNX-6352 for axatilimab will be computed. |
| 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) | To determine if the size and number of target lesions changes in response to treatment with axatilimab by analyzing CT-Scans/MRIs per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) and irRECIST. |
| Phase 1a: Effect of Axatilimab on CSF-1 and IL-34 | 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 |
| Phase 1a: Evaluate the immunogenicity of Axatilimab | Approximately 6 months (from first dose to End of Treatment visit) | To assess the immunogenicity of axatilimab as measured by presence of anti-drug antibodies (ADA) |
| Phase 1b: PK endpoint of Cmax (maximum observed concentration) for Axatilimab when given in combination with a fixed dose of durvalumab as dose levels increase across different treatment groups. | Approximately 6 months (from first dose to End of Treatment visit) | Cmax for axatilimab will be computed. |
| Phase 1b: PK endpoint of Tmax (time to reach maximum observed concentration) for Axatilimab when given in combination with a fixed dose of durvalumab as dose levels increase across different treatment groups. | Approximately 6 months (from first dose to End of Treatment visit) | Tmax for axatilimab will be computed. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Phase 1b: Exploration of relationship between additional biomarkers and anti-tumor activity of Axatilimab when given in combination with a fixed dose of durvalumab. | 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 axatilimab when given in combination with a fixed dose of durvalumab. |
| Phase 1b: Characterization of relationship in change from baseline in CSF-1, IL-34, etc. with Axatilimab administered intravenously when given in combination with a fixed dose of durvalumab. | Approximately 6 months (from first dose to End of Treatment visit) | To characterize the relationship in change from baseline in plasma colony stimulating factor-1 \[CSF-1\] interleukin-34 \[IL-34\]), and IFN-gamma, IL-1beta, IL-2, IL-4, IL-5, IL-6, CXCL8/IL-8, IL-10, IL-12 (p70), IL-13, TNF-alpha, CD204/206 and sCD163 with systemic PK of axatilimab administered intravenously when given in combination with a fixed dose of durvalumab. |
| Phase 1b:Effect of Axatilimab when given in combination with a fixed dose of durvalumab on CSF-1 receptor occupancy. | Approximately 6 months (from first dose to End of Treatment visit) | To evaluate the change from Baseline in CSF-1 receptor occupancy (RO). |
| Phase 1a: Effect of Axatilimab on CSF-1 receptor occupancy | Approximately 6 months (from first dose to End of Treatment visit) | To evaluate the change from Baseline in CSF-1 receptor occupancy (RO) |
| Phase 1b: Characterization of the PD profile of Axatilimab and durvalumab when given in combination. | Approximately 6 months (from first dose to End of Treatment visit) | To characterize the pharmacodynamic (PD) profile of axatilimab and durvalumab when given in combination in patients with advanced solid tumors. |
| Phase 1a: Characterization of relationship in change from baseline in CSF-1, IL-34, etc. with Axatilimab administered intravenously. | Approximately 6 months (from first dose to End of Treatment visit) | To characterize the relationship in change from baseline in plasma colony stimulating factor-1 \[CSF-1\] interleukin-34 \[IL-34\]), and IFN-gamma, IL-1beta, IL-2, IL-4, IL-5, IL-6, CXCL8/IL-8, IL-10, IL-12 (p70), IL-13, TNF-alpha, CD204/206 and sCD163 with systemic PK of axatilimab administered intravenously. |
| 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) | 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 axatilimab |
| 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) | To investigate the relationship between candidate biomarkers (e.g., CSF-1, IL-34) and anti-tumor activity of axatilimab |
| Phase 1b: Exploration of relationship between candidate biomarker results and anti-tumor activity of Axatilimab when given in combination with a fixed dose of durvalumab. | 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 axatilimab when given in combination with a fixed dose of durvalumab. |
Countries
United States
Outcome results
None listed