Advanced Solid Tumors, Recurrent or Progressive Glioblastoma, Relapse or Refractory Myeloid Malignancies
Conditions
Brief summary
This is a Phase 1, open-label, dose-escalation study of CBX-663 in participants with R/R AML, MDS or CMML (Cohort A), advanced solid tumors (Cohort B), or recurrent or progressive GBM (Cohort C) (collectively called 'indication cohorts'). Participants aged ≥18 years are planned to be enrolled. CBX-663 will initially be investigated on a fixed dosing schedule. CBX-663 will be administered intravenously (IV) on Cycle 1 Day 1 (C1D1) and then once weekly (QW) in 21-day cycles. Participants will continue treatment with CBX-663 until unacceptable toxicity, progressive disease, withdrawal of consent, or lack of clinical benefit.
Interventions
DRUGCBX-663
Intravenous (I.V.) CBX-663
Sponsors
Crossbow Therapeutics, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Cohort A (R/R AML, MDS or CMML) Specific Inclusion Criteria: 1. R/R AML, as defined by standardized criteria (e.g., European Leukemia Net criteria (Dohner, 2022) (Arber, 2022); after standard of care therapy. Participants with persistent leukemia after initial therapy or with recurrence of leukemia at any time after achieving a response during or after the course of treatment (including HSCT) are eligible. Participants must have bone marrow blasts ≥5%. 2. R/R MDS as per WHO 2022. Participants must have peripheral or bone marrow blasts \<20%, and must have exhausted locally available treatments, including treatments for actionable mutations. a. For High-Risk MDS participants, participants must be resistant to or refractory to at least 4 cycles of hypomethylating agents or have progressed or are intolerant to such agents. 3. R/R dysplastic or proliferative CMML participants, participants must be resistant or refractory to 4-6 cycles of hypomethylating agents (HMA; decitabine or azacitidine). 4. White blood cells must be below 25,000/µL at time of enrollment. Participants may receive cytoreduction prior to enrollment. 5. Any prior treatment-related toxicities resolved to Grade ≤1 prior to enrollment, with the exception of Grade ≤2 alopecia. Cohort B (Solid Tumor) Specific Inclusion Criteria: 6. Histologically or cytologically diagnosed, locally advanced (unresectable) or metastatic solid cancers that have progressed after all available standard therapy for the specific tumor type, or for which no standard therapy exists. Participants for whom standard therapies are intolerable or considered inappropriate by the Investigator are eligible. 7. Measurable disease (as defined by RECIST version 1.1). Prior Therapy 8. Any prior treatment-related toxicities resolved to Grade ≤1 prior to enrollment, with the exception of Grade ≤2 alopecia. 9. Steroids: At least 7 days since systemic glucocorticoid therapy, unless receiving physiologic dosing (equivalent to ≤10 mg prednisone daily) or cytoreductive therapy. Cytoreductive therapy must have approval of the Study Responsible Physician. 10. Hematopoietic Growth Factors: At least 7 days since the completion of therapy with short-acting hematopoietic growth factors and 14 days with long-acting growth factors. 11. Anti-Cancer Therapy: Chemotherapy or small molecule targeted therapy, either investigational or commercially approved and available, within 2 weeks or 5 half-lives (whichever is shorter) prior to the start of study drug administration. 12. Radiation Therapy: At least 60 days from prior total body irradiation, craniospinal radiation and/or ≥50% radiation of the pelvis, or at least 14 days from local palliative radiation therapy (small port). Cohort C (Recurrent/Progressive GBM) Specific Inclusion Criteria: 13. Histologically confirmed or molecularly defined diagnosis of glioblastoma (IDH-wildtype) according to WHO 2021. 14. Historical documented evidence of a TERT promoter mutation. 15. Radiographic evidence of recurrent or progressive disease following prior first-line radiotherapy, defined as progression per RANO 2.0 criteria, as determined by investigator assessment. Prior use of tumor-treating fields is allowed but not required (Wen, 2023). 16. Measurable (at least 1 cm x 1 cm) enhancing tumor. 17. Any prior treatment-related toxicities resolved to ≤Grade 1 prior to enrollment, with the exception of ≤Grade 2 alopecia and ≤Grade 2 fatigue. Inclusion Criteria for All Participants: 18. Aged ≥18 years. 19. Backfill Cohorts: Participants for whom no curative treatment options, including transplantation, are available. 20. Historical documented evidence of HLA-A\*02:01 allele positivity. 21. ECOG PS score 0-1. Adequate Organ Function Requirements within 10 Days of Treatment Initiation 22. Estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2 based on local institutional practice (e.g., Cockcroft-Gault formula). 23. Adequate liver function defined as: * Total bilirubin \<1.5 × the upper limit of normal (ULN) for age or normal conjugated bilirubin, or total bilirubin ≤ 3.0 x ULN with direct bilirubin within normal range in participants with well documented Gilbert's syndrome or hemolysis or who require regular blood transfusions. * Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) \<3 × ULN (unless attributed to leukemic or tumor involvement with discussion with the Study Responsible Physician). 24. If a female of childbearing potential, willing to use a highly effective method of contraception or double barrier method from the time of enrollment through 120 days following the last study drug dose. 25. If male of childbearing potential, agrees to use barrier contraception from the time of enrollment through 120 days following the last study drug dose. 26. Participant or participant's health care proxy is able and willing to provide written informed consent and able to follow study instructions.
Exclusion criteria
Cohort C (Recurrent/Progressive GBM) Specific
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| To assess the PK of CBX-663: AUC0-t | Approximately 1 year. | Area under the plasma concentration-time curve from time 0 to time of last measurable concentration (AUC0-t) of CBX-663 and relevant metabolites. |
| To assess the preliminary anti-leukemic activity of CBX-663 in participants with R/R AML (Cohort A): | From enrollment through 30 days following end of treatment | Objective response rate (ORR), complete response (CR), CR with partial hematologic recovery (CRh), CR with incomplete hematologic recovery (CRi) (Dohner, 2022) CR rate (CR+CRh) CRc Rate (CR+ CRh + CRi) |
| To assess the preliminary anti-leukemic activity of CBX-663 in participants with R/R CMML (Cohort A) | From enrollment through 30 days following end of treatment. | Response criteria for CMML: evaluated per IWG 2015 (Savona, 2015) in adults with endpoints including CR, PR, complete cytogenetic remission, marrow response and clinical benefit as appropriate |
| To assess the preliminary anti-leukemic activity of CBX-663 in participants with R/R MDS (Cohort A): | From enrollment through 30 days following end of treatment. | Best Overall Response (BOR) as defined by MDS/MPN International Working Group (IWG) 2023 (Zeidan, 2023) for Higher-Risk MDS and IWG 2018 (Platzbecker, 2019) for Lower-Risk MDS |
| To assess the preliminary anti-leukemic activity of CBX-663 in participants in Cohort A: Duration of Response (DoR) | From enrollment through 30 days following end of treatment. | To assess the duration of response (DoR) of CBX-663. |
| To assess the preliminary anti-leukemic activity of CBX-663 in participants in Cohort A: Time to Response (TTR) | From enrollment through 30 days following end of treatment. | To assess the time to response (TTR) of CBX-663. |
| To assess the preliminary anti-leukemic activity of CBX-663 in participants with R/R AML, MDS or CMML (Cohort A): CRminimal residual disease (MRD)- rate for participants with CRc. | From enrollment through 30 days following end of treatment. | To assess the CRminimal residual disease (MRD)- rate for participants with CRc of CBX-663. |
| To assess the preliminary anti-leukemic activity of CBX-663 in Cohort A: Hematologic Improvement (HI) | From enrollment through 30 days following end of treatment. | HI defined as: * Not meeting criteria for CR (or CR equivalent) or CRuni or CRL * HIerythroid (HI-E) * HIplatelets (HI-P) * HIneutrophils (HI-N) |
| To assess the preliminary anti-leukemic activity of CBX-663 in Cohort A: Transfusion Independence | From enrollment through 30 days following end of treatment. | Transfusion independence defined as any transfusion-free period lasting for at least 56 consecutive days, during which the participant is either on CBX-663 therapy or after cessation of CBX-663 therapy but prior to the start of new therapy. |
| To assess the preliminary anti-leukemic activity of CBX-663 in Cohort A: Transfusion burden reduction | From enrollment through 30 days following end of treatment. | To assess the transfusion burden reduction of CBX-663. |
| To assess the preliminary anti-leukemic activity of CBX-663 in Cohort A: Rate of leukemic transformation | From enrollment through 30 days following end of treatment. | To assess the rate of leukemic transformation of CBX-663. |
| To assess the preliminary anti-leukemic activity of CBX-663 in Cohort A: Event free survival (EFS) | From enrollment through 30 days following end of treatment. | To assess the Event free survival (EFS) of CBX-663. |
| To assess the preliminary anti-leukemic activity of CBX-663 in Cohort A: Overall Survival (OS) | From enrollment through 30 days following end of treatment. | To assess the Overall Survival (OS) of CBX-663. |
| To assess the preliminary anti-tumor activity of CBX-663 in Cohort B based on Investigator assessment using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria: Overall Response Rate (ORR) | From enrollment through 30 days following the end of treatment. | To assess overall response rate (ORR) of CBX-663. |
| To assess the preliminary anti-tumor activity of CBX-663 in Cohort B based on Investigator assessment using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria: Duration of Response (DoR) | From enrollment through 30 days following end of treatment. | To assess duration of response of CBX-663. |
| To assess the preliminary anti-tumor activity of CBX-663 in Cohort B based on Investigator assessment using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria: Time to Response (TTR) | From enrollment through 30 days following end of treatment. | To assess time to response (TTR) of CBX-663. |
| To assess the preliminary anti-tumor activity of CBX-663 in Cohort B based on Investigator assessment using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria: Disease Control Rate (DCR) | From enrollment through 30 days following end of treatment. | To assess disease control rate (DCR) of CBX-663. |
| To assess the preliminary anti-tumor activity of CBX-663 in Cohort B based on Investigator assessment using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria: Progression Free Survival (PFS) | From enrollment through 30 days following end of treatment. | To assess progression free survival (PFS) of CBX-663. |
| To assess the preliminary anti-tumor activity of CBX-663 in Cohort B based on Investigator assessment using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria: Overall Survival (OS) | From enrollment through 30 days following end of treatment. | To assess overall survival (OS) of CBX-663. |
| To assess the preliminary anti-tumor activity of CBX-663 in participants with recurrent/progressive GBM (Cohort C): Overall Response Rate (ORR) | From enrollment through 30 days following the end of treatment. | To assess the overall response rate (ORR) per Response Assessment in Neuro-Oncology (RANO) Criteria 2.0 (Wen 2023) and iRANO |
| To assess the preliminary anti-tumor activity of CBX-663 in Cohort C: Duration of Response (DoR) | From enrollment through 30 days following end of treatment. | To assess duration of response (DoR) of CBX-663. |
| To assess the preliminary anti-tumor activity of CBX-663 in Cohort C: Time to Response (TTR) | From enrollment through 30 days following end of treatment. | To assess time to response (TTR) of CBX-663. |
| To assess the preliminary anti-tumor activity of CBX-663 in Cohort C: Disease Control Rate (DCR) | From enrollment through 30 days following end of treatment. | To assess disease control rate of CBX-663. |
| To assess the preliminary anti-tumor activity of CBX-663 in Cohort C: Progression Free Survival (PFS) | From enrollment through 30 days following end of treatment. | To assess progression free survival (PFS) of CBX-663. |
| To assess the preliminary anti-tumor activity of CBX-663 in Cohort C: Overall Survival (OS) | From enrollment through 30 days following end of treatment. | To assess overall survival (OS) of CBX-663. |
| To assess the preliminary anti-tumor activity of CBX-663 in Cohort C: Changes in Corticosteroid Use | From enrollment through 30 days following end of treatment. | To assess changes in corticosteroid use in participants with GBM. |
| To assess the preliminary anti-tumor activity of CBX-663 in Cohort C: Changes in neurologic function as assessed by the Neurological Assessment in Neuro-Oncology scale | From enrollment through 30 days following end of treatment. | To assess changes in neurologic function as assessed by the Neurological Assessment in Neuro-Oncology scale in participants with GBM. |
| To assess the PK of CBX-663: Degree of accumulation | Approximately 1 year. | Degree of CBX-663 accumulation in the blood stream and body. |
| To assess the PK of CBX-663: Cmax | Approximately 1 year. | Maximum plasma concentration (Cmax) of CBX-663 and relevant metabolites. |
| To assess the PK of CBX-663: Tmax | Approximately 1 year. | Time to observed maximum plasma concentration of CBX-663 and relevant metabolites |
| To assess the PK of CBX-663: Ctau | Approximately 1 year. | CBX-663 drug concentration at the end of the dosing interval. |
| To assess the PK of CBX-663: T½ | Approximately 1 year. | Terminal elimination half-life of CBX-663. |
| Recommended Phase 2 Dose (RP2D) | Until the end of study (approximately 24 months) | To determine the RP2D. |
| To determine safety and tolerability of CBX-663; Dose Limiting Toxicities (DLTs), Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related Adverse Events (TRAEs). | From enrollment through 30 days following end of treatment. | Frequency and type of dose-limiting toxicities (DLT), Frequency, duration, and severity of treatment-emergent adverse events (TEAEs), treatment-related AEs (TRAEs), and serious adverse events (SAEs), Frequency and severity of cytokine release syndrome (CRS) adverse events (AEs), Withdrawal from the study, drug discontinuations, drug interruptions, or dose reductions due to adverse events Incidence/shifts of clinical laboratory abnormalities |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| To assess the immunogenicity of CBX-663. | From enrollment through 30 days following the end of treatment. | Incidence and severity of anti-drug antibodies (ADAs) |
Countries
United States
Outcome results
None listed