AML - Acute Myeloid Leukemia, Chronic Myeloid Leukemia, Chronic Myelomonocytic Leukemia (CMML), High-risk Myelodysplastic Syndrome
Conditions
Keywords
AML, HR-MDS, CMML, acute leukemia, CBX-250, CBX-250-001, CROSSCHECK, CROSSCHECK-001, Crossbow, CML
Brief summary
Study CBX-250-001 is a Phase 1, open-label, dose-escalation study of CBX-250 in participants with relapsed/refractory AML, HR-MDS, CMML, and CML. Participants aged ≥ 12 years are planned to be enrolled. CBX-250 will initially be investigated on a fixed step-up dosing schedule. CBX-250 will be administered subcutaneously in 28-day cycles, with the first study drug dose administered on Cycle 1, Day 1. Cycle 1 will consist of a priming phase over 7 days, and a target phase over 28 days. Participants will continue CBX-250 until progressive disease (PD) or unacceptable toxicity. All subsequent treatment cycles will be 28 days.
Interventions
DRUGCBX-250
subcutaneous CBX-250
Sponsors
Crossbow Therapeutics, Inc.
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Participants are eligible to be included in the study only if all of the following criteria apply: Age 1. Dose Escalation: Male or female participants aged ≥18 years. 2. Backfill Cohorts: Male or female participants aged ≥12 years for whom no curative treatment options, including transplantation, are available. Diagnosis \& Disease Characteristics 3. Participants with histological confirmation of advanced hematologic malignancy including: 1. R/R AML, as defined by standardized criteria (e.g., European LeukemiaNet criteria \[Dohner 2022\]; 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. 2. R/R HR-MDS or very high risk MDS as per the Revised International Prognostic Scoring System (IPSS-R; Greenberg 2012) or Molecular International Prognostic Scoring System (IPPS-M, Bernard 2022) who are resistant or refractory to 4-6 cycles of hypomethylating agents (HMA; decitabine or azacitidine). 3. R/R CMML who are 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. Historical documented evidence of HLA-A\*02:01 allele positivity. Performance Level 6. ECOG PS score 0-1 (if aged ≥18 years); Karnofsky Performance Scale of ≥70 (if aged ≥16 years and \<18 years); Lansky PS of ≥70 (if aged \<16 years). Prior Therapy 7. Any prior treatment-related toxicities resolved to ≤Grade 1 prior to enrollment, with the exception of ≤Grade 2 alopecia. 8. 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). 9. Stem Cell Infusion: At least 60 days must have elapsed from HSCT and at least 4 weeks (from first dose) must have elapsed from donor lymphocyte infusion without conditioning. 10. Immunotherapy: At least 42 days since prior immunotherapy, including tumor vaccines and checkpoint inhibitors, and at least 21 days since receipt of chimeric antigen receptor therapy. 11. Anti-Leukemia Therapy: At least 14 days since the completion of anti-leukemic therapy (for example, but not limited to, small molecule or cytotoxic/myelosuppressive therapy), with the following exceptions: * Hydroxyurea for cytoreduction can be initiated without restriction related to timing of study entry. Hydroxyurea for cytoreduction can be continued concomitantly with CBX-250, with Study Responsible Physician approval. * Intrathecal chemotherapy at the time of diagnostic lumbar puncture at least 24 hours prior to the start of CBX-250 and may continue prophylactic intrathecal chemotherapy beginning in Cycle 2, at the treating physician's discretion. 12. 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. 13. Biologics (e.g. monoclonal antibody therapy): At least 28 days or 5 half-lives, whichever is shorter, have elapsed since the completion of therapy with a biologic agent. Any AE related to prior biologic treatment must be resolved to baseline severity or ≤Grade 1. 14. 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. Adequate Organ Function Requirements within 10 Days of Treatment Initiation 15. Estimated glomerular filtration rate ≥ 45 mL/min/1.73 m2 based on local institutional practice for age-appropriate determination (eg, Schwartz formula for pediatric participants or Cockcroft-Gault formula for adults). 1. Participants ≥18 years: glomerular filtration rate ≥45 mL/min 2. Participants \<18 years: ≥45 mL/min x (participant's body surface area m2/1.73) • 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 involvement with discussion with the Study Responsible Physician). Sex and Contraceptive/Barrier Requirements 16. 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. 17. If male of childbearing potential, agrees to use barrier contraception from the time of enrollment through 120 days following the last study drug dose. Informed Consent 18. Participant or participant's health care proxy is able and willing to provide written informed consent and able to follow study instructions.
Exclusion criteria
Participants are excluded from the study if any of the following criteria apply: Diagnosis 1. Previous CTSG targeted therapy or treatment with any pMHC T-cell engager. 2. Isolated extramedullary relapse. 3. Active central nervous system (CNS) disease. Participants with prior CNS history can be enrolled if the participant has a negative lumbar puncture following completion of intrathecal chemotherapy). Infection 4. Known HIV infection. 5. Active hepatitis B infection (participants with documented clearance following treatment are allowed). 6. Active hepatitis C infection (participants with documented clearance following treatment are allowed). Pregnancy and Breastfeeding 7. Pregnant or nursing women: Negative serum pregnancy tests are required during Screening and a negative serum or urine pregnancy test is required within 72 hours prior to receiving the first study drug administration, in females of childbearing potential. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. Concurrent Conditions 8. Cardiac Disease: * Any of the following within the 6 months prior to study entry: myocardial infarction, uncontrolled/unstable angina, congestive heart failure (New York Heart Association Classification Class \>II), life-threatening, uncontrolled arrhythmia, cerebrovascular accident, or transient ischemic attack. * QTc using Fridericia's correction (QTcF) \>480 msec 9. Graft-Versus-Host Disease (GVHD): Active acute or chronic GVHD requiring systemic treatment with immunosuppressive medication. Participants may be on physiological doses of steroids. 10. Concurrent malignancy in the previous 2 years with the exception of basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (eg, breast carcinoma, cervical cancer in situ, melanoma in situ) treated with potentially curative therapy. Concurrent malignancy must be in CR or no evidence of disease (NED) during this timeframe. 11. History of or any concurrent condition, therapy, or laboratory abnormality that in the Investigator's opinion might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate. Concomitant Medications and Interventions 12. Any commercially available or investigational anti-leukemic therapy other than CBX-250, with the following exceptions: • Intrathecal chemotherapy for CNS prophylaxis is permitted after C1 is complete, at the treating physician's discretion. 13. Participation in another therapeutic interventional clinical study in which an investigational agent was administered within 14 days or 5-halflives, whichever is shorter, of starting CBX-250. Participants may continue with non-interventional follow-up from previous clinical studies. 14. Any concurrent systemic treatment to prevent GVHD. Topical treatments for GVHD are permitted. 15. Known allergy or sensitivity to study drug, including excipients.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| To determine the safety, tolerability, RP2D, or MTD if different, and dosing regimen of CBX-250. | Until the end of study (approximately 24 months) | Frequency and type of DLT |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| AUC0-t (first dose and at steady state) | Approximately 1 year | Area under the plasma concentration-time curve from time 0 to time of last measurable concentration (AUC0-t) of CBX-250 and relevant metabolites |
| Cmax | Approximately 1 year | Maximum plasma concentration (Cmax) of CBX-250 and relevant metabolites |
| Tmax | Approximately 1 year | Time to observed maximum plasma concentration of CBX-250 and relevant metabolites |
| ADAs | Approximately 1 year | Incidence and severity of anti-drug antibodies |
| ORR | Approximately 1 year | To assess the overall response rate (ORR) of CBX-250 |
| CR+CRh rate in AML | Approximately 1 year | To assess the complete remission (CR) and complete remission with partial hematologic recovery (CRh) rate |
| EFS | Approximately 3 years | To assess the event free survival (EFS) of CBX-250 |
| OS | Approximately 3 years | To assess overall survival (OS) of CBX-250 |
| DOR | Approximately 3 years | To assess the duration of response (DOR) of CBX-250 |
| CRc rate in AML | Approximately 3 years | To assess the composite definition of complete remission (CRc) rate |
| Remission rate in HR-MDS | Approximately 1 year | Remission rate as defined by Zeidan 2023: CR, CR equivalent, partial remission (PR), CRL (CRuni and CRbi), CRh, Hematologic improvement (HI) |
| PFS | Approximately 3 years | To assess the progression free survival (PFS) of CBX-250 |
| CR+CRh rate in HR-MDS | Approximately 1 year | CR+ CR equivalent+ CRL + CRh |
| Transfusion independence | Approximately 3 years | Any transfusion-free period lasting for at least 56 consecutive days, during which the participant is either on CBX-250 therapy or after cessation of CBX-250 therapy but prior to the start of new therapy |
| To assess the preliminary anti-leukemic activity of CBX-250 in participants with CMML | Approximately 1 year. | Proportion of participants achieving complete response (CR), complete cytogenetic remission, partial response (PR), marrow response, and clinical benefit according to the 2015 International Consortium Proposal of Uniform Response Criteria for Myelodysplastic Syndromes (MDS)/Myeloproliferative Neoplasms (MPN). |
| To assess the preliminary anti-CML activity of CBX-250 in participants with CML | Approximately 1 year. | Proportion of participants achieving a ≥1-log10 reduction in BCR::ABL1 transcript levels from pre-treatment baseline at Week 12 (Day 169 ± 7 days), measured on the International Scale (IS) by centralized realtime quantitative PCR (RT-qPCR) |
Countries
United States
Contacts
CONTACTRachel Ghiraldi
STUDY_CHAIRBriggs Morrison, MD
Crossbow Therapeutics, Inc.
Outcome results
None listed