AMLM26/T4 INTERCEPT
A multi-arm trial for patients with acute myeloid leukaemia investigating new treatments which target early relapse and changes in disease characteristics – SNDX5613
Acute Myeloid Leukaemia
The ALLG AMLM26 INTERCEPT trial is an adaptive trial allowing the testing of multiple new therapeutic options targeting various AML biomarkers in a staged manner. The Master Protocol outlines the overall study structure (this is detailed in ANZCTR entry ACTRN12621000439842). There will be separate domains for each AML biomarker being investigated. Each domain will have at least one investigational agent. Each investigational agent may be used on its own and/or in combination with other agents. Each option will be a different treatment arm within a domain. Separate Therapy-Specific Protocol Appendices will include treatment-specific information for each investigational agent including all of the treatment arms specific to that investigational agent. Each treatment arm may be targeted to a specific AML biomarker (domain) and/or may be used when patients have no targetable option available. This entry is for the investigational agent SNDX5613. This will have 1 treatment arm – SNDX5613 alone.
SNDX5613 is a capsule that will be administered orally twice a day. Taken on an empty stomach at least 2 hours after a meal or 1 hour before the next meal. Administered days 1-28 of a 28 days cycle for 12 cycles.
As this agent has not yet been tested in patients with MRD progression, we will confirm the dose for patients with MRD progression in a pilot safety run-in phase. The first dose level explored will be 276mg twice a day. If not tolerable 226mg twice a day will be investigated, and if that is not tolerable 163mg twice a day will be investigated.
Once the optimal dose is determined in the pilot phase for MRD progressors, enrolment onto a proof of concept phase will commence using the dose level deemed tolerable.
Patients in the morphologic relapse will immediately be enrolled into the POC phase at a dose of 276mg twice a day SNDX-5613 from days 1-28 of a 28-day cycle (utilising the recommended phase 2 dose determined by the SNDX- 5613 sponsored phase 1b/II study (NCT04065399) to be most tolerable and effective).
Key inclusion criteria
1. Meets inclusion criteria outlined in the AMLM26 INTERCEPT Master Protocol (see ACTRN12621000439842 for details on the master protocol)
2. Presence of MLL-r or PTD, or NPM1 mutation in a bone marrow or peripheral blood sample taken no more than 28 days prior to cycle 1 of day 1 of treatment on this treatment arm. Patients with MLL-r with mixed-phenotype acute leukaemia (MPAL) will also be considered eligible for this study
3. ECOG 0-2
4. Confirmation of serum potassium greater than or equal to 3.6 mmol/L and serum magnesium greater than or equal to 0.66 mmol/L within one week before first dose of study drug, at which time oral supplementation can be started to maintain potassium greater than or equal to 4.0 and magnesium greater than or equal to 0.82 to meet electrolyte thresholds for SNDX5613 dosing. Subject must have adequate renal function as demonstrated by a creatinine clearance greater than or equal to 60 mL/min; calculated by the Cockcroft Gault formula or measured by 24-hours urine collection
6. Adequate cardiac function defined as left ventricular ejection fraction (EF) of greater than 50% by echocardiogram or multi-gated acquisition (MUGA) scan.
7. Subject must have adequate liver function as demonstrated by:
a. aspartate aminotransferase (AST) less than or equal to 3.0 × ULN
b. alanine aminotransferase (ALT) less than or equal to 3.0 × ULN
c. bilirubin less than or equal to 1.5 × ULN (unless bilirubin rise is due to Gilbert’s syndrome or of non- hepatic origin)
8. Agrees to follow the recommended contraception procedures for this treatment arm
2. Presence of MLL-r or PTD, or NPM1 mutation in a bone marrow or peripheral blood sample taken no more than 28 days prior to cycle 1 of day 1 of treatment on this treatment arm. Patients with MLL-r with mixed-phenotype acute leukaemia (MPAL) will also be considered eligible for this study
3. ECOG 0-2
4. Confirmation of serum potassium greater than or equal to 3.6 mmol/L and serum magnesium greater than or equal to 0.66 mmol/L within one week before first dose of study drug, at which time oral supplementation can be started to maintain potassium greater than or equal to 4.0 and magnesium greater than or equal to 0.82 to meet electrolyte thresholds for SNDX5613 dosing. Subject must have adequate renal function as demonstrated by a creatinine clearance greater than or equal to 60 mL/min; calculated by the Cockcroft Gault formula or measured by 24-hours urine collection
6. Adequate cardiac function defined as left ventricular ejection fraction (EF) of greater than 50% by echocardiogram or multi-gated acquisition (MUGA) scan.
7. Subject must have adequate liver function as demonstrated by:
a. aspartate aminotransferase (AST) less than or equal to 3.0 × ULN
b. alanine aminotransferase (ALT) less than or equal to 3.0 × ULN
c. bilirubin less than or equal to 1.5 × ULN (unless bilirubin rise is due to Gilbert’s syndrome or of non- hepatic origin)
8. Agrees to follow the recommended contraception procedures for this treatment arm
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Presence of any general exclusion criteria outlined in the AMLM26 INTERCEPT Master Protocol (see ACTRN12621000439842 for details on the master protocol)
2. QT-interval corrected according to Fridericia’s formula (QTcF) greater than 450ms on triplicate ECGs (each separated by 2 minutes with average of 3 ECGs used to calculate QTcF interval).
3. Subject is HIV positive and has detectable HIV viral PCR and/or with signs of active/uncontrolled infection. Patients who are HIV-positive with undetectable viral load are eligible provided that anti-retroviral used is not a prohibited medication on study.
4. Prior allogeneic stem cell transplantation within 60 days of post-conditioning or on immunosuppression or greater than 10mg/day prednisolone for graft vs host disease (GVHD). Patients must have been off systemic immunosuppressive therapy (apart from stated prednisolone dose above) for at least 4 weeks prior to enrolment.
5. Evidence of other clinically significant uncontrolled condition(s) including, but not limited to:
a. Uncontrolled and/or active systemic infection (viral, bacterial or fungal)
b. Chronic hepatitis B virus (HBV) or hepatitis C (HCV) requiring treatment. Note: subjects with serologic evidence of prior vaccination to HBV (i.e. hepatitis B surface (HBs) antigen negative-, anti-HBs antibody positive and anti-hepatitis B core (HBc) antibody negative) or positive anti-HBc antibody from intravenous immunoglobulins (IVIG) or patients who have past exposure to HepB (HepB Surface Antigen negative but core antibody positive and DNA negative) who do not require treatment may participate.
6. Patients who have ingested seville oranges, grapefruit or grapefruit juice and/or kumquats, pomegranate or pomegranate juice, pomelos, exotic citrus fruit (i.e., star fruit, bitter melon), grapefruit hybrids or fruit juices, or other foods and juices known to inhibit CYP3A4 within three days prior to initiation of study treatment, and are not willing to cease their ingestion for the duration of the study.
7. Treatment with any of the following within 7 days prior to the first dose of study drug:
a. Steroid therapy for anti-neoplastic intent or on greater than 10mg/day prednisolone for graft versus host disease
b. Moderate or strong CYP3A inducers
c. CYP3A inhibitors:
• SAFETY RUN-IN PHASE PATIENTS: Moderate and strong cytochrome CYP3A inhibitors are prohibited 7 days prior to cycle 1 day 1 and during cycle 1 of the safety run-in phase.
• PROOF OF CONCEPT (POC) AND EXPANSION PHASE PATIENTS: Moderate and strong cytochrome CYP3A4 inhibitors with the exception of posaconazole, voriconazole, itraconazole or ketoconazole are prohibited 7 days prior to cycle 1 day 1. Patients on azole antifungals should have been on it for greater than or equal to 7 days prior to first dose of SNDX-5613.
8. Treatment with prior anti-leukemic therapy within 5 half-lives or 14 days (whichever is shorter) prior to the first dose of study drug (except steroids see exclusion 7a).
9. Subject has been diagnosed with another malignancy, unless disease-free for at least 2 years and not needing active treatment. Patients with fully excised BCC/SCC/CIN or other minor malignancy are not excluded.
10. Subject has clinically significant abnormality of coagulation profile, such as disseminated intravascular coagulation
11. Subject has had any of the following within 6 months prior to screening: myocardial infarction, uncontrolled/unstable angina, congestive heart failure New York Heart Association (NYHA) class 3 or 4, uncontrolled arrhythmia, cerebrovascular accident, or transient ischemic attack.
12. Patients unable to swallow oral medications, or with gastrointestinal issues which might affect oral drug absorption or ingestion (i.e, gastroparesis, etc)
2. QT-interval corrected according to Fridericia’s formula (QTcF) greater than 450ms on triplicate ECGs (each separated by 2 minutes with average of 3 ECGs used to calculate QTcF interval).
3. Subject is HIV positive and has detectable HIV viral PCR and/or with signs of active/uncontrolled infection. Patients who are HIV-positive with undetectable viral load are eligible provided that anti-retroviral used is not a prohibited medication on study.
4. Prior allogeneic stem cell transplantation within 60 days of post-conditioning or on immunosuppression or greater than 10mg/day prednisolone for graft vs host disease (GVHD). Patients must have been off systemic immunosuppressive therapy (apart from stated prednisolone dose above) for at least 4 weeks prior to enrolment.
5. Evidence of other clinically significant uncontrolled condition(s) including, but not limited to:
a. Uncontrolled and/or active systemic infection (viral, bacterial or fungal)
b. Chronic hepatitis B virus (HBV) or hepatitis C (HCV) requiring treatment. Note: subjects with serologic evidence of prior vaccination to HBV (i.e. hepatitis B surface (HBs) antigen negative-, anti-HBs antibody positive and anti-hepatitis B core (HBc) antibody negative) or positive anti-HBc antibody from intravenous immunoglobulins (IVIG) or patients who have past exposure to HepB (HepB Surface Antigen negative but core antibody positive and DNA negative) who do not require treatment may participate.
6. Patients who have ingested seville oranges, grapefruit or grapefruit juice and/or kumquats, pomegranate or pomegranate juice, pomelos, exotic citrus fruit (i.e., star fruit, bitter melon), grapefruit hybrids or fruit juices, or other foods and juices known to inhibit CYP3A4 within three days prior to initiation of study treatment, and are not willing to cease their ingestion for the duration of the study.
7. Treatment with any of the following within 7 days prior to the first dose of study drug:
a. Steroid therapy for anti-neoplastic intent or on greater than 10mg/day prednisolone for graft versus host disease
b. Moderate or strong CYP3A inducers
c. CYP3A inhibitors:
• SAFETY RUN-IN PHASE PATIENTS: Moderate and strong cytochrome CYP3A inhibitors are prohibited 7 days prior to cycle 1 day 1 and during cycle 1 of the safety run-in phase.
• PROOF OF CONCEPT (POC) AND EXPANSION PHASE PATIENTS: Moderate and strong cytochrome CYP3A4 inhibitors with the exception of posaconazole, voriconazole, itraconazole or ketoconazole are prohibited 7 days prior to cycle 1 day 1. Patients on azole antifungals should have been on it for greater than or equal to 7 days prior to first dose of SNDX-5613.
8. Treatment with prior anti-leukemic therapy within 5 half-lives or 14 days (whichever is shorter) prior to the first dose of study drug (except steroids see exclusion 7a).
9. Subject has been diagnosed with another malignancy, unless disease-free for at least 2 years and not needing active treatment. Patients with fully excised BCC/SCC/CIN or other minor malignancy are not excluded.
10. Subject has clinically significant abnormality of coagulation profile, such as disseminated intravascular coagulation
11. Subject has had any of the following within 6 months prior to screening: myocardial infarction, uncontrolled/unstable angina, congestive heart failure New York Heart Association (NYHA) class 3 or 4, uncontrolled arrhythmia, cerebrovascular accident, or transient ischemic attack.
12. Patients unable to swallow oral medications, or with gastrointestinal issues which might affect oral drug absorption or ingestion (i.e, gastroparesis, etc)
Dr. Carolyn Grove
Australasian Leukaemia & Lymphoma Group
Phase 1 / Phase 2
AMLM26/T4 INTERCEPT
ACTRN12622000582752