Phase 1 Study of Ziftomenib with Chemotherapy in Pediatric Relapsed/Refractory KMT2A-r, NUP98-r, or NPM1-m Acute Leukemia
- Trial ID
- 2023-505262-28-00
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to determine the recommended phase 2 dose (**RP2D**) of **ziftomenib** in combination with chemotherapy (FLA) for pediatric patients with relapsed or refractory **KMT2A-rearranged**, **NUP98-rearranged**, or **NPM1-mutant** acute leukemia. This objective is clinically relevant as it aims to establish a safe and effective dosing regimen that could potentially improve treatment outcomes for children with these specific genetic subtypes of acute leukemia.
Secondary objectives include:
- Describing the safety and tolerability of ziftomenib when administered with chemotherapy (FLA) and/or a second cycle if needed.
- Evaluating the safety and tolerability profile during prolonged exposure (up to 12 cycles of 28 days) to ziftomenib.
- Assessing the safety and tolerability profile in patients receiving ziftomenib post-hematopoietic stem cell transplant (**HSCT**), with a maximum of 12 cycles.
- Determining the pharmacokinetics (**PK**) of ziftomenib, including its relationship to age.
- Describing the HSCT rate.
- Describing the anti-leukemic activity in pediatric patients with relapsed or refractory KMT2A-r, NUP98-r, or NPM1-m acute leukemia, both overall and per disease subset (acute myeloid leukemia (**AML**) and acute lymphocytic leukemia (**ALL**)).
Participants
The clinical trial involves a total of **10 participants** diagnosed with **Acute Myeloid Leukemia**, **Mixed Phenotype Acute Leukemia**, or **Acute Lymphocytic Leukemia**. The study population includes both male and female subjects, with an age range from 0 to 21 years, and a minimum of 80% of participants being under 18 years of age. Participants were selected based on their diagnosis of relapsed or refractory KMT2A-r, NUP98-r, or NPM1-m acute leukemia. The trial population is characterized by a vulnerable group, including children and young adults, who have previously undergone various anti-cancer therapies. Participants must have recovered from the acute toxic effects of prior treatments and meet specific health criteria, such as adequate renal, liver, and cardiac function. Lifestyle considerations, such as diet and physical activity, are not specified, but female participants of childbearing potential must adhere to contraceptive guidelines, and breastfeeding is not permitted during the study. The trial aims to determine the recommended phase 2 dose of ziftomenib in combination with chemotherapy in this specific patient population.
Plans and Procedures
The clinical trial is designed to evaluate the safety and pharmacokinetics of **ziftomenib** in combination with chemotherapy in pediatric patients with relapsed or refractory acute leukemia, specifically targeting KMT2A-rearranged, NUP98-rearranged, or NPM1-mutant subtypes. This is a Phase 1 trial employing a randomized, double-blind, controlled methodology to determine the recommended phase 2 dose (RP2D) of ziftomenib. The trial is expected to commence recruitment on November 1, 2024, and is estimated to conclude by December 31, 2028.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on specific criteria, including age, prior therapy recovery, and adequate organ function. Following successful screening, participants will be enrolled and randomized to receive either the investigational treatment or control. The trial will include multiple follow-up visits to monitor dose-limiting toxicities (DLTs) and pharmacokinetic parameters during the first cycle of treatment. Secondary endpoints will assess adverse events, overall response rates, and survival metrics.
The expected duration of participant involvement will vary depending on individual response and tolerance to the treatment, with the possibility of early termination if significant adverse events occur or if the participant withdraws consent. Conditions leading to early termination include severe adverse reactions or non-compliance with study protocols. The end-of-study visit will involve comprehensive assessments to evaluate the overall safety and efficacy of the treatment regimen. Participants are required to adhere to contraceptive guidelines and must not have received certain prior therapies within specified timeframes before enrollment.
Treatment
The clinical trial involves the administration of **Ziftomenib**, an experimental medication, which is a menin inhibitor. Ziftomenib is provided in the form of a hard capsule and is administered orally. The active substance, ziftomenib, is chemically synthesized and is identified by the sponsor product code KO-539. The medication is not a pediatric formulation and is designated as an orphan drug under the designation number EU/3/23/2881. The frequency and specific dosage of administration are determined based on the trial protocol, with compliance monitored throughout the study.
In addition to Ziftomenib, the trial includes the administration of **Cytarabine**, a standard chemotherapy agent. Cytarabine is provided as a 20 mg/ml solution for injection or infusion and is administered intravenously. The active substance, cytarabine, is also chemically synthesized. This medication is used as part of the chemotherapy regimen in the trial, and its administration is conducted according to established dosing schedules for chemotherapy.
Another chemotherapy agent used in the trial is **Fludarabine Phosphate**, provided as a 25 mg/ml concentrate for solution for injection or infusion. This medication is administered intravenously. Fludarabine phosphate is chemically synthesized and is used in combination with other chemotherapy agents as part of the treatment protocol. The administration schedule is aligned with standard chemotherapy practices.
Additionally, **Solu-Cortef**, containing the active substance **Hydrocortisone**, is used as an auxiliary treatment. Solu-Cortef is provided as a powder for solution for injection or infusion, with a concentration of 100 mg. It is administered via intrathecal use. Hydrocortisone is chemically synthesized and serves as a supportive therapy in the trial, with administration tailored to the needs of the participants as per the trial protocol.
Efficacy
Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint focuses on determining the recommended phase 2 dose (RP2D) of **ziftomenib** in combination with chemotherapy, based on dose-limiting toxicities (DLTs) observed during the first cycle of treatment and pharmacokinetic parameters, specifically the area under the curve (AUC) of **ziftomenib**. Secondary endpoints include the characterization of adverse events (AEs) by type, frequency, severity, timing, seriousness, and relation to study therapy, as graded using CTCAE version 5.0. Additionally, the pharmacokinetics of **ziftomenib** in combination with FLA chemotherapy will be evaluated, including parameters such as Cmax, Cmin, Tmax, AUC0-t, AUC0-∞, CL/F, Vz/F, and t½.
Further secondary endpoints involve the assessment of the rate of patients proceeding to subsequent hematopoietic stem cell transplantation as consolidation therapy, calculated as the number of patients receiving a hematopoietic stem cell infusion divided by the total number of patients enrolled and started treatment. The study will also evaluate morphological overall response rate (ORR), flow-based ORR, flow-based measurable residual disease (MRD) negativity rate, duration of response (DOR), event-free survival (EFS) one year after the end of treatment (EOT) of the last patient with **ziftomenib**, overall survival (OS) one year after EOT, and cumulative incidence of relapse (CIR) one year after EOT. These efficacy parameters will be measured and analyzed at specified timepoints throughout the trial to ensure comprehensive evaluation of the treatment's impact on the patient population.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Age: 0-21 years (and at least 5 kg BW), with a minimum of 80% of patients under 18 years of age
- Eligible patients also must fulfill one of the following conditions: Refractory disease/induction failure: a) AML: The bone marrow contains ≥ 5% leukemic blasts by local morphology at the end of 2 cycles of induction therapy. ALL/MPAL/AUL: The bone marrow contains ≥ 5% leukemic blasts by local morphology MFC at the end of induction and consolidation
- Performance Status: Patients must have a performance status corresponding to ECOG scores of 0, 1 or 2 (≥ 50% Lansky or Karnofsky score). Use ECOG for adult patients (≥18 to 21 years), Karnofsky for patients ≥16 to 18 years of age, and Lansky for patients < 16 years of age. Patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.
- Adequate Organ Function: a) Renal Function Defined as: creatinine clearance (CrCl) ≥60 mL/min (as measured by a nuclear glomerular filtration rate [GFR] scan or calculated by the Schwartz formula (APPENDIX III The Schwartz formula) and normalized to a body surface area of 1.73 m2)[71]. b) Liver Function Defined as: • Direct bilirubin < 3 x ULN and SGPT (ALT) ≤ 5 x ULN. • If liver abnormality is due to radiographically identifiable leukemia infiltrate, the patient will remain eligible. c) Cardiac function defined as: Pre-treatment left ventricular function on echocardiography: FS ≥ 25% or EF ≥ 40%, and no signs of congestive heart failure within 4 weeks before start of screening.
- Prior Therapy: Patients must have recovered from the acute toxic effects of all prior anti-cancer Therapy (excluding Grade 2 toxicities that are not considered a safety risk or medically significant toxicity deemed irreversible by the Investigator) and must meet the following minimum duration from prior anti-cancer directed therapy prior to enrollment. a) Cytotoxic chemotherapy: Must not have received within 14 days or within 5 drug half-lives (whichever is longer), of entry onto this study, except for hydroxyurea or corticosteroids. Use of steroids and hydroxyurea for other purposes such as differentiation syndrome, or to premedication to prevent allergic reaction or during anesthesia is allowed.
- Prior Therapy: Patients must have recovered from the acute toxic effects of all prior anti-cancer Therapy (excluding Grade 2 toxicities that are not considered a safety risk or medically significant toxicity deemed irreversible by the Investigator) and must meet the following minimum duration from prior anti-cancer directed therapy prior to enrollment. b) Intrathecal cytotoxic therapy: No washout or waiting period is required for patients having received any combination of intrathecal cytarabine, methotrexate, and/or hydrocortisone.
- Prior Therapy: Patients must have recovered from the acute toxic effects of all prior anti-cancer Therapy (excluding Grade 2 toxicities that are not considered a safety risk or medically significant toxicity deemed irreversible by the Investigator) and must meet the following minimum duration from prior anti-cancer directed therapy prior to enrollment. c) Antibodies: ≥ 21 days must have elapsed from infusion of last dose of an antibody-drug conjugate. For unmodified antibodies or T cell engaging antibodies, 2 half-lives must have elapsed before enrollment. Any toxicity related to prior antibody therapy must be recovered back to baseline.
- Informed Consent: Written, signed and dated informed consent and pediatric assent (if applicable) according to local law and legislation should be collected before start of any study procedures
- Female patients of childbearing potential must have a negative urine or serum pregnancy test confirmed prior to enrollment.
- Female patients with infants must agree not to breastfeed their infants while on this study.
- Contraception: a. Patients of reproductive potential, starting from menarche and onwards, may not participate unless they have agreed to use a highly effective contraceptive method per Clinical Trial Facilitation Group (CTFG) guidelines for the duration of study therapy and for 6 months after the completion of all study therapy. For further guidance please review the CTFG website. b. Male patients must use a condom during intercourse and agree not to father a child or donate sperm during therapy and for the duration of study therapy and for 6 months after the completion of all study therapy.
- Prior Therapy: Patients must have recovered from the acute toxic effects of all prior anti-cancer Therapy (excluding Grade 2 toxicities that are not considered a safety risk or medically significant toxicity deemed irreversible by the Investigator) and must meet the following minimum duration from prior anti-cancer directed therapy prior to enrollment. d) Interleukins, interferons and cytokines (other than hematopoietic growth factors): ≥ 21 days after the completion of interleukins, interferon or cytokines (other than hematopoietic growth factors).
- Prior Therapy: Patients must have recovered from the acute toxic effects of all prior anti-cancer Therapy (excluding Grade 2 toxicities that are not considered a safety risk or medically significant toxicity deemed irreversible by the Investigator) and must meet the following minimum duration from prior anti-cancer directed therapy prior to enrollment. e) Hematopoietic growth factors: ≥ 14 days after the last dose of a long-acting growth factor (e.g., peg-filgrastim) or 7 days for short-acting growth factor.
- Prior Therapy: Patients must have recovered from the acute toxic effects of all prior anti-cancer Therapy (excluding Grade 2 toxicities that are not considered a safety risk or medically significant toxicity deemed irreversible by the Investigator) and must meet the following minimum duration from prior anti-cancer directed therapy prior to enrollment. f) Radiation therapy (RT): 14 days have elapsed for local palliative RT (small port); ≥ 84 days must have elapsed if prior craniospinal RT or if ≥ 50% radiation of pelvis; ≥ 42 days must have elapsed if other substantial BM radiation.
- Prior Therapy: Patients must have recovered from the acute toxic effects of all prior anti-cancer Therapy (excluding Grade 2 toxicities that are not considered a safety risk or medically significant toxicity deemed irreversible by the Investigator) and must meet the following minimum duration from prior anti-cancer directed therapy prior to enrollment. Stem Cell Infusions: a. Patients who have relapsed after allogeneic (non-autologous) bone marrow or stem cell transplant (with or without TBI) or boost infusion (any stem cell product; not including DLI) must be at least 84 days post HSCT and without evidence of GVHD of any severity except: the use of topical steroids for cutaneous GVHD is allowed and stable steroid doses less than or equal to 10 mg of prednisone daily is permitted. Prednisone dose must be adjusted for BSA in young children. Physiologic doses of hydrocortisone for patients with adrenal insufficiency is allowed. b. Patients who after relapse and continue to receive cyclosporine, tacrolimus or other agents to treat or prevent either graft-versus-host disease post bone marrow transplant or organ rejection post-transplant are not eligible for this trial. In the relapse setting, patients must be off medications to treat or prevent either graft-versus-host disease post bone marrow transplant or organ rejection post-transplant for at least 14 days prior to enrollment. A stable steroid dose as mentioned above is allowed.
- Prior Therapy: Patients must have recovered from the acute toxic effects of all prior anti-cancer Therapy (excluding Grade 2 toxicities that are not considered a safety risk or medically significant toxicity deemed irreversible by the Investigator) and must meet the following minimum duration from prior anti-cancer directed therapy prior to enrollment. h) Cellular therapy: ≥ 30 days after the completion of DLI (donor lymphocyte infusion) or any type of cellular Therapy (e.g., modified T cells, NK cells, dendritic cells, etc.).
- Prior Therapy: Patients must have recovered from the acute toxic effects of all prior anti-cancer Therapy (excluding Grade 2 toxicities that are not considered a safety risk or medically significant toxicity deemed irreversible by the Investigator) and must meet the following minimum duration from prior anti-cancer directed therapy prior to enrollment. i) Prior exposure to a different menin inhibitor: Patients who received previous treatment with a different menin inhibitor are allowed to enrol in the study with the exception of those who experienced a severe adverse event attributable to the strong anti-proliferative/pro-differentiation effects of other menin inhibitors (such as severe differentiation syndrome). Patients who experienced a severe adverse event, which can directly be attributed to specific effects (e.g., long QT syndrome) observed with other menin inhibitors can participate in the study if they fulfill the inclusion criteria.
- Diagnosis: KMT2A-r, NPM1-m, or NUP98-r acute leukemia in first or greater relapse or refractory to standard (re-) induction treatment (including HSCT).
- Eligible patients also must fulfill one of the following conditions: • First or subsequent relapse: a) Bone marrow relapse is defined as: i) a single bone marrow sample or bone biopsy showing ≥ 5% leukemic blasts by local morphology b) Patients with combined extramedullary and bone marrow relapse (defined as above) are eligible. c) d) Patients with asymptomatic CNS3 disease are eligible if they do not have isolated CNS3 extramedullary relapse, see for definition section 7.8.
- Enrollment APAL2020SC trial (US and Canada only): Patients in the US and Canada must have enrolled in the APAL2020SC trial prior to enrollment in the APAL2020K trial.
Exclusion Criteria
- Patients who in the opinion of the investigator may not be able to comply with the study requirements of the study.
- Patients with Down syndrome.
- Patients with isolated extramedullary disease (EMD) are not eligible. EMD relapse is defined as biopsy proven extramedullary disease without bone marrow disease after documented CR following initial therapy.
- Patients with isolated CNS relapse are not eligible, as well as symptomatic CNS3 disease.
- Patients with acute promyelocytic leukemia (APL) or juvenile myelomonocytic leukemia (JMML).
- Patients with malabsorption syndrome or any other condition that precludes enteral administration of a menin inhibitor.
- Concommittant Therapy: Gastric pH has great influence on absorption of ziftomenib; therefore, the use of proton pump inhibitors is prohibited, if necessary H2 Blockers may provide an alternative treatment option (for details see chapter 1.6 drug-drug interactions)
- Patients who are currently receiving another investigational drug.
- Patients with any known congenital bone marrow failure syndrome.
- Patients with known prior allergy to any of the medications used in protocol therapy.
- Patients with documented active, uncontrolled infection at the time of study entry.
- Active/uncontrolled known human immunodeficiency virus (HIV) infection, HBV and HCV. Note: HIV testing does not need to be conducted at screening unless it is required per local guidelines or institutional standard.
- Post menarche female patients with positive pregnancy test, and a lactating female patient.
- Patient has a pre-existing disorder predisposing the patient to a serious or life-threatening infection (e.g., cystic fibrosis, congenital or acquired immunodeficiency, bleeding disorder, or cytopenia not related to the leukemia or its treatment).
- Patients must not be receiving other investigational medications (defined as medicinal products not yet approved for any indications, including alternative/herbal therapies) within 30 days of first dose of study drug or while on study.
- Significant congenital cardiovascular disease including, but not limited to conditions such as long QT syndrome, fundamental uncorrected cardiac defect (e.g., coarctation of the aorta) that poses a significant risk to the patient (ventricular septal defect or atrial septal defect are considered non-significant).
- Underlying medical condition that, in the Principal Investigator’s opinion, will make the administration of study treatment hazardous or obscure the interpretation of toxicity determination or adverse events (AEs).
- For fluadarabine and cytarabine: Hypersensitivity to the active substance or to any of the excipients
- Recent live vaccinations for at least 6 months.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Recruiting | 01 Nov 2024 | 2 |
 France | Recruiting | 01 Nov 2024 | 2 |
 Italy | Recruiting | 01 Nov 2024 | 2 |
 The Netherlands | Recruiting | 01 Nov 2024 | — |
 Spain | Recruiting | 01 Nov 2024 | 2 |
| Netherlands | — | — | 2 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Ziftomenib | Test | CAPSULE, HARD | ORAL | — | — | PRD11093836 |
Ziftomenib | Test | CAPSULE, HARD | ORAL | — | — | PRD8079333 |
Cytarabine 20 mg/ml Solution for Injection/Infusion | Test | SOLUTION FOR INJECTION/INFUSION | INTRAVENOUS | — | — | PRD7370525 |
Fludarabine phosphate 25 mg/ml Concentrate for Solution for Injection or Infusion | Test | CONCENTRATE FOR SOLUTION FOR INJECTION OR INFUSION | INTRAVENOUS | — | — | PRD1794901 |
Ziftomenib | Test | CAPSULE, HARD | ORAL | — | — | PRD8079332 |
Cytarabine 20 mg/ml Solution for Injection/Infusion | Test | SOLUTION FOR INJECTION/INFUSION | INTRAVENOUS | — | — | PRD7370526 |
Solu-Cortef Powder for Solution for Injection or Infusion 100 mg | Other | POWDER FOR SOLUTION FOR INJECTION OR INFUSION | INTRATHECAL USE | — | — | PRD1179840 |