Combining SL-401 with Azacitidine or Venetoclax for treating blood cancers

Phase 1 Study of SL-401 in Combination With Azacitidine and Venetoclax in Relapsed/Refractory Acute Myeloid Leukemia (AML) and in Treatment-Naive Subjects With AML Not Eligible for Standard Induction and in Subjects With Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN) or SL-401 in Combination With Azacitidine in Subjects With High-Risk Myelodysplastic Syndrome (MDS)

This study is testing if combining a new treatment called SL-401 with existing drugs azacitidine or venetoclax can help people with certain blood cancers feel better and improve their outcomes.

Quick facts

• Phase: Phase 1
• Study type: Interventional
• Enrollment: 72 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Dana-Farber Cancer Institute (Academic / other)
• Drugs / interventions: chemotherapy, radiation
• Locations: 3 sites (Duarte, California and 2 other locations)
• Trial ID: NCT03113643 on ClinicalTrials.gov

What this trial studies

This Phase I clinical trial investigates the safety and optimal dosing of SL-401 when combined with azacitidine or azacitidine/venetoclax in patients with acute myeloid leukemia (AML), high-risk myelodysplastic syndrome (MDS), or blastic plasmacytoid dendritic cell neoplasm (BPDCN). The study aims to determine if this combination can effectively treat these cancers by targeting cancer stem cells. While azacitidine and venetoclax are FDA-approved for AML, their combination with SL-401 is not yet approved, making this trial crucial for assessing new treatment options.

Who should consider this trial

Good fit: Ideal candidates include adults aged 18 and older with relapsed or refractory AML, treatment-naïve AML who are unfit for intensive chemotherapy, high-risk MDS, or relapsed BPDCN.

Not a fit: Patients with early-stage or non-relapsed forms of these conditions may not benefit from this study.

Why it matters

Potential benefit: If successful, this treatment combination could provide a new therapeutic option for patients with difficult-to-treat blood cancers.

How similar studies have performed: Other studies have shown promise in using similar combinations for treating blood cancers, but this specific approach is novel.

Eligibility criteria

Inclusion Criteria:

Histologically confirmed diagnosis of acute myeloid leukemia (AML) \[Cohort B\] or myelodysplastic syndrome (MDS) \[Cohort A\] or BPDCN \[Cohort C\] per 2016 WHO criteria

CD123 / IL3RA expression on the subject's AML or MDS blasts or BPDCN cells determined locally within 3 months of first protocol treatment

Age \>= 18 years with relapsed or refractory AML (hydroxyurea is not considered a prior treatment regimen) \[Cohort B\]

OR

Age \>= 18 years with treatment-naïve AML who decline intensive induction chemotherapy or who are unfit due to co-morbidity or other factors (see APPENDIX A for unfitness definitions) (hydroxyurea is not considered a prior treatment regimen) \[Cohort B\]

OR

Age \>= 18 years with MDS and \> 10% myeloblasts in the bone marrow \[Cohort A\]

OR

Age \>= 18 years with relapsed or refractory BPDCN (hydroxyurea is not considered a prior treatment regimen) \[Cohort C\]

Adequate organ function as defined by:

Albumin \> 3.2 g/dL (in the absence of receipt of intravenous albumin in the previous 72 hours) Serum creatinine \< 1.5x ULN Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) \< 2.5x ULN Total bilirubin \< 1.5x ULN (if thought to be \> 1.5x ULN due to Gilbert's disease or the patient's AML, must discuss with the PI) Creatine phosphokinase (CPK) \< 2.5x ULN Left ventricular ejection fraction \> institutional lower limit of normal by MUGA scan or echocardiogram within 30 days of first protocol treatment

\[Cohorts B and C\] WBC \< 20,000 / uL on day of first therapy, cytoreduction may be achieved using hydroxyurea

Ability to understand and the willingness to sign a written informed consent document.

Able to adhere to study visit schedule and other protocol requirements including follow-up for survival assessment

Women of child-bearing potential must agree to use adequate contraception for the duration of study participation and for 2 months after completion of protocol treatment.

Men treated or enrolled on this protocol must also agree to use adequate contraception for the duration of study participation and 2 months after completion of protocol treatment.

Exclusion Criteria:

Prior treatment with venetoclax \[Cohorts B or C\], unless it was last taken \>2 months before protocol therapy

Diagnosis of acute promyelocytic leukemia

Received treatment with chemotherapy, radiation, or biologic cancer therapy within 14 days of first protocol treatment, except for intrathecal chemotherapy. Prior and concurrent hydroxyurea is permitted.

Hematopoietic stem cell transplantation (HSCT) within 60 days of screening or active graft versus-host-disease

Active CNS involvement by AML or BPDCN. Screening lumbar puncture (LP) required for patients with BPDCN. If history of treated CNS involvement, must have had two consecutive negative LPs since last CNS involvement, which may include the screening LP

Known positive status for HIV infection; known active hepatitis B or hepatitis C infection

Clinically significant cardiopulmonary disease including uncontrolled or NYHA class 3 or 4 congestive heart failure, uncontrolled angina, uncontrolled hypertension, uncontrolled arrhythmia, myocardial infarction or stroke within 6 months of first protocol treatment, or QTc \> 480 ms

Patients with known active advanced malignant solid tumors are excluded (except for basal or squamous skin cancers, or carcinomas in situ). Patients with additional hematologic malignancies that require treatment are excluded.

Pregnant women are excluded from this study because there is an unknown but potential risk for adverse events in the developing fetus with SL-401, azacitidine, and venetoclax (negative urine or serum pregnancy test required within 14 days of Cycle 1, Day 1). Because nursing infants have unknown potential for adverse events secondary to treatment of the mother, breastfeeding should be discontinued if the mother is treated with SL-401, azacitidine, and venetoclax.

Patients with uncontrolled infection shall not be enrolled until infection is treated and brought under control. Patients with active infection are permitted to enroll provided that the infection is controlled

\[Cohorts B and C\] Patients with gastrointestinal (GI) tract disease causing the inability to take oral medication, malabsorption syndrome, a requirement for intravenous (IV) alimentation, prior surgical procedures affecting absorption, uncontrolled inflammatory GI disease (e.g., Crohn's disease, ulcerative colitis)

\[Cohorts B and C\] Patients on strong CYP3A inducers within 7 days of first dose of study treatment.

Where this trial is running

Duarte, California and 2 other locations

• City of Hope — Duarte, California, United States (Recruiting)
• Dana Farber Cancer Institute — Boston, Massachusetts, United States (Recruiting)
• MD Anderson Cancer Center — Houston, Texas, United States (Recruiting)

Study contacts

• Principal investigator: Andrew Lane, MD, PhD — Dana-Farber Cancer Institute
• Study coordinator: Andrew Lane, MD, PhD

Conditions Acute Myeloid Leukemia; Myelodysplastic Syndrome; Blastic Plasmacytoid Dendritic Cell Neoplasm; BPDCN