| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsed or Refractory Acute Leukemias |
|
| E.1.1.1 | Medical condition in easily understood language |
| Relapsed or Refractory Acute Leukemias |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10024330 |
| E.1.2 | Term | Leukemia acute |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Phase 1
The objectives for Phase 1 of this study apply to all arms unless otherwise stated in the objective.
• To determine the safety, tolerability, maximum tolerated dose (MTD), and recommended Phase 2 dose (RP2D) of SNDX-5613 in patients with relapsed/refractory (R/R) acute leukemia in each of the arms studied.
• To characterize the pharmacokinetics (PK) parameters of SNDX-5613 and relevant metabolites in each of the arms studied.
Phase 2
• To evaluate short- and long-term safety and tolerability of SNDX-5613.
• To assess the complete remission (CR)+ complete remission with partial hematologic recovery (CRh) rate. |
|
| E.2.2 | Secondary objectives of the trial |
Phase 1
To compare the PK parameters of SNDX-613 and relevant metabolites when administered in a tablet formulation compared with a capsule formulation.
Phase 2
• To assess postbaseline transfusion independence.
• To assess the composite definition of complete remission (CRc) rate [CR + CRh + complete remission with incomplete hematologic recovery (CRi) + complete remission with incomplete platelet recovery (CRp)].
• To assess the overall response rate (ORR) (CRc + morphological leukemia-free state [MLFS] + partial remission [PR]).
• To assess the time to response (TTR), duration of response (DOR), and event free survival (EFS).
• To assess overall survival (OS).
• To characterize PK parameters of SNDX-5613 and relevant metabolites. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Diagnosis:
1. Patients in Phase 1 Arm A and Arm B must have active acute leukemia harboring Lysine (K) methyltransferase 2A (KMT2A) rearrangement or Nucleophosmin 1 mutation (NPM1) mutation as defined by the National Comprehensive Cancer Network (NCCN) Guidelines stated in the protocol.
Patients in Phase 1 Arm C, Arm D, Arm E and Arm F must meet one of the following 2 criteria:
•active acute leukemia (bone marrow blasts ≥5% or reappearance of blasts inperipheral blood) as defined by the NCCN Guidelines stated in the protocol.
•acute leukemia harboring an KMT2A rearrangement, Nucleoporin 98 (NUP98) rearrangement, or NPM1 mutation that have detectable disease in the bone marrow not meeting criterion for active leukemia as described above.
2. Phase 1:
• Arm A: Patients must not be receiving any strong CYP3A4 inhibitor/inducers or fluconazole. Patients who were receiving a strong CYP3A4 inhibitor/inducer or fluconazole must have discontinued the medication at least 7days prior to enrollment.
• Arm B: Patients must be receiving itraconazole, ketoconazole, posaconazole, or voriconazole for antifungal prophylaxis for at least 7days prior to enrollment and while on SNDX-5613 treatment. Patients must not be receiving any other strong CYP3A4 inhibitors/inducers.
• Arm C: Patients must weigh ≥35 kg and be willing to receive daily cobicistat from C1D2 for at least 28 days. Patients must not be receiving any other weak, moderate, or strong CYP3A4 inhibitors/inducers. Patients who were receiving a moderate/strong CYP3A4 inhibitor/inducer must have discontinued the medication at least 7days prior to enrollment.
•Arm D: Patients must be receiving fluconazole for at least 7days prior to enrollment and while on SNDX-5613 treatment. Patients must not be receiving any other weak, moderate or strong CYP3A4 inhibitors/inducers.
•Arms E: Patients must not be receiving any weak, moderate, or strong CYP3A4 inhibitors/inducers for at least 7 days prior to enrollment and while on SNDX5613 treatment.
• Arm F: Patients must be receiving isavuconazole for at least 7 days prior to enrollment and while on SNDX-5613 treatment. Patients must not be receiving any other weak, moderate, or strong CYP3A4 inhibitors/inducers.
3. Phase 2: Documented R/R active acute leukemia.
• Cohort 2A: Documented R/R ALL/MPAL with a KMT2A rearrangement.
• Cohort 2B: Documented R/R AML with a KMT2A rearrangement.
• Cohort 2C: Documented R/R AML with NPM1m.
Mutational status is to be reviewed locally to determine patient eligibility in Phase 2 and confirmed centrally.
Disease Status:
4. Recurrent or refractory AML/ALL or MPAL, as defined by standardized criteria after standard of care therapy, including but not limited to one or two cycles of intensive chemotherapy, or venetoclax combinations. Patients 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 are eligible. Refractory or relapsed leukemia is defined by presence of ≥5% blasts in the bone marrow and/or persistence or reappearance of peripheral blasts. Patients who have <5% blasts in the bone marrow at baseline may be replaced to ensure a sufficient number of patients for the efficacy analyses.
Age/Weight:
5. Male or female patient aged ≥6 months. Patients intended to receive SNDX-5613 in combination with cobicistat must weigh ≥35 kg. See Protocol Section 10.11.3.1 for age of inclusion criteria in Germany.
Performance Level:
6. Eastern Cooperative Oncology Group (ECOG) performance status score 0–2 (if aged ≥18 years); Karnofsky Performance Scale of ≥50 (if aged ≥16 years and <18 years); Lansky Performance Score of ≥50 (if aged ≥12 years and <16 years). See Protocol Section 10.11.3.1 for ECOG performance status criteria in Germany.
Prior Therapy:
7. Any prior treatment-related toxicities resolved to ≤Grade 1 prior to enrollment, with the exception of ≤Grade 2 neuropathy or alopecia.
8. Radiation Therapy: At least 60days from prior total body irradiation (TBI), craniospinal radiation and/or ≥50% radiation of the pelvis, or at least 14days from local palliative radiation therapy.
9. Stem Cell Infusion: At least 60 days must have elapsed from hematopoietic stem cell transplant (HSCT) and at least 4 weeks must have elapsed from donor lymphocyte infusion (DLI).
10. Immunotherapy: At least 42days since prior immunotherapy, including tumor vaccines, and at least 21days since receipt of chimeric antigen receptor therapy or other modified T or Natural KIller (NK) cell therapy.
11. Antileukemia Therapy: At least 14days, or 5 half-lives, whichever is shorter, since the completion of antileukemic therapy with the exceptions as defined in the protocol.
12. Hematopoietic Growth Factors: At least 7days since the completion of therapy with short-acting hematopoietic growth factors and 14days with long-acting growth factors.
See protocol for additional inclusion criteria. |
|
| E.4 | Principal exclusion criteria |
Diagnosis:
1. Diagnosis of active acute promyelocytic leukemia.
2. Isolated extramedullary relapse (Phase 2 only).
3. Active CNS disease. Refer to the protocol for further details.
Infection:
4. Detectable human immunodeficiency virus (HIV) viral load within the previous 6 months. Patients with a known history of HIV 1/2 antibodies must have viral load testing prior to study enrollment.
5. Hepatitis B (defined as hepatitis B virus [HBV] surface antigen positive and HBV core antibody positive, or positive HBV deoxyribonucleic acid [DNA].
6. Hepatitis C (defined as positive hepatitis C [HCV] antibody with reflex to positive HCV ribonucleic acid [RNA]).
Pregnancy and Breast-Feeding:
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, life-threatening, uncontrolled arrhythmia, cerebrovascular accident, or transient ischemic attack.
• QTc using Fridericia’s correction >450 msec.
9. Gastrointestinal (GI) Disease:
• Any GI issue of the upper GI tract likely to affect oral drug absorption or ingestion.
• Cirrhosis with a Child-Pugh score of B or C.
10. Graft-Versus-Host Disease (GVHD): Signs or symptoms of acute or chronic GVHD >Grade 0 within 4 weeks of enrollment. All transplant patients must have been off all systemic immunosuppressive therapy and calcineurin inhibitors for at least 4 weeks prior to enrollment. Patients may be on physiological doses of steroids.
11. 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 treated with potentially curative therapy, or concurrent low-grade lymphoma, that is asymptomatic and lacks bulky disease and shows no evidence of progression, and for which the patient is not receiving any systemic therapy or radiation.
12. Concurrent malignancy must be in complete remission or no evidence of disease during this timeframe.
13. History of or any concurrent condition, therapy, laboratory abnormality, or allergy to excipients that in the Investigator’s opinion might confound the results of the study, interfere with the patient’s participation for the full duration of the study, or is not in the best interest of the patient to participate.
Concomitant Medications and Interventions:
14. Any commercially available or investigational antileukemic therapy other than SNDX-5613, with exceptions as defined in the protocol.
15. Please refer to the protocol for the list of exclusion that apply to related to concomitant use of CYP3A4 inhibitors or inducers (Phase 1 and Phase 2).
16. Phase 1 and Phase 2: Patients requiring the concurrent use of medications known or suspected to prolong the QT/QTc interval, with the exception of drugs with low risk of QT/QTc prolongation that are used as standard supportive therapies and the azoles permitted in the relevant arms of Phase 1 and in Phase 2. Please see Appendix 10.7 of the protocol for examples of medications that may be appropriate substitutes for such medications.
Please refer to the protocol for additional exclusion criteria. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase 1:
• Occurrence of dose-limiting toxicities (DLTs).
• Frequency, duration, and severity of treatment-emergent adverse events (TEAEs), treatment-related TEAEs (TRAEs), and serious adverse events (SAEs).
• Incidence and shifts of clinically significant clinical laboratory abnormalities.
• Change from baseline in other observations related to safety, including electrocardiograms (ECGs), vital signs, ophthalmologic examination findings, and performance status.
• Pharmacokinetic (PK) parameters: maximum plasma concentration (Cmax), time to maximum plasma concentration (Tmax), area under the plasma concentration versus time curve (AUC) from time 0 to t (AUC0–t), AUC from time 0 to 24 hours (AUC0–24), apparent oral clearance (CL/F), apparent volume of distribution (Vz/F), and half-life (t1/2).
In Phase 1, the study endpoints will be assessed by dose cohort and overall. and will apply to all arms unless otherwise stated in the endpoint.
Phase 2:
• CR+CRh rate.
• Frequency, duration, and severity of TEAEs, TRAEs, and SAEs.
• Incidence and shifts of clinically significant clinical laboratory abnormalities.
• Change from baseline in other observations related to safety, including ECGs, vital signs, ophthalmologic examination findings, and performance status.
For Phase 2, endpoints will be assessed by disease cohort (2A, 2B, and 2C separately) and pooled MLLr population |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
AEs: BL, C1(Day 3/4, 7/8, 10/11, 14/15, 17/18, 21/22), C2(D1,D15), ≥C3D1, EoT, f/up
ECG: SCR, BL, C1(Day 1, 2, 3/4, 7/8, 14/15, 21/22), C2D15, ≥C3D1, f/up
Holter Monitoring (Phase I): BL
Vital signs: SCR, BL, C1(Day 1, 2, 3/4, 7/8, 10/11, 14/15), C2(D1,D15), C3D1, EoT, f/up
Ophthalmologic exam: SCR, ≥C3D1, EoT, f/up
Performance Status: SCR, BL, ≥C2D1, C3D1, f/up
Hematology: SCR, BL, C1(D 3/4, 7/8, 10/11, 14/15, 17/18, 21/22), ≥C2D1, C3D1, EoT, f/up
Clinical Chemistry: SCR, BL, C1(Day 2, 3/4, 7/8, 10/11, 14/15, 17/18, 21/22); ≥C2D1, C3D1, EoT, f/up
Urinalysis: C1D1/BL, C2D1, C3D1, f/up
PK: BL, C1(Day 2, 3/4, 7/8, 14/15), C2 (Day 8, 15), ≥C3D1
Coagulation panel: SCR
C=Cycle; D=day; SCR=screening; BL=Baseline; EoT=End of Treatment; f/up=Safety follow-up |
|
| E.5.2 | Secondary end point(s) |
Phase 1:
• PK parameters for tablet vs. capsule evaluation: Cmax, Tmax, AUC0–t, AUC0–24, CL/F, Vz/F, t1/2.
Phase 2:
• Transfusion independence, defined as any transfusion-free period lasting for at least 56 consecutive days, during which the patient is either on SNDX-5613 therapy or after cessation of SNDX-5613 therapy but prior to the start of new therapy.
• CRc rate (ie, CR+CRh+CRi+CRp).
• ORR (CRc+MLFS+PR).
• Time to response.
• Duration of response.
• Event free survival.
• Overall survival.
• PK parameters: Cmax, Tmax, AUC0–t, AUC0–24, CL/F, Vz/F, and t1/2. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Disease assessments: throughout the duration of the study.
PK: as above |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.5.1 | Number of sites anticipated in the EEA | 13 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Canada |
| Israel |
| United States |
| France |
| Germany |
| Italy |
| Lithuania |
| Netherlands |
| Spain |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
Last visit of the last subject.
Note that after the Safety Follow-up visit all patients will be followed for long-term survival status via telephone contact or office visit until death or closure of the study by the Sponsor. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 20 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 20 |
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