| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Adult patients with relapsed or refractory IDH1-mutated AML or relapsed/refractory MSD/AML with 10-19% bone marrow blasts at initial diagnosis and at screening (ECOG 0-2) after at least one prior line of treatment (including intensive chemotherapy,at least 2 cycles of hypomethylating agents or low-dose cytarabine, and alloHCT),who are not eligible for intensive chemotherapy including alloHCT can be recruited and will be treated with the PHD inhibitor molidustat and the IDH1 inhibitor ivosidenib. |
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| E.1.1.1 | Medical condition in easily understood language |
| The clinical trial will investigate whether combination therapy of molidustat and ivosidenib is safe and can improve treatment outcomes in patients suffering from IDH1-mutated AML or MDS. |
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| 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 | 27.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10028533 |
| E.1.2 | Term | Myelodysplastic syndrome |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| 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 |
The primary objectives of the study are:
• Phase Ia: To determine the recommended phase II dose of molidustat (RP2D) based on the DLT rate observed for up to three investigated doses.
• Phase IIb: To establish initial efficacy by assessing the CR rate of the combination treatment including molidustat and ivosidenib.
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| E.2.2 | Secondary objectives of the trial |
secondary objectives:
•To assess the combined rate of CR, CR with partial hematologic recovery (CRh) and CR with incomplete hematologic recovery (CRi).
•To assess the proportion of patients becoming transfusion-independent
•To evaluate EFS, OS, RFS, CIR, and CID after CR/CRh/CRi of the combination treatment including molidustat and ivosidenib.
•To evaluate minimal residual disease (MRD) status at sequential time points throughout treatment and CR/CRh/CRiMRD− rate of the combination of molidustat and ivosidenib using molecular techniques (IDH1 mutation and other molecular markers).
•To evaluate limited pharmacodynamics (PD) of molidustat (erythropoietin induction) and ivosidenib (R-2HG inhibition).
safety objectives:
•To assess safety and tolerability comparing the frequency and severity of (severe) adverse events according to CTCAE criteria.
•To evaluate the proportion of patients requiring phlebotomy (hematocrit ≥ 45%)
•To evaluate 30 and 60 day mortality rates
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patients eligible for inclusion in this study have to meet all of the following criteria:
1. Age ≥ 18 years.
2. Patients with diagnosis of relapsed or refractory AML (≥5% bone marrow blasts, and/or ≥1% peripheral blood blasts, and/or histologically proven extramedul-lary disease) defined according to 2022 ICC criteria1 after at least one prior line of treatment who are ineli-gible for intensive salvage chemotherapy and/or al-logeneic hematopoietic cell transplantation or who decline standard treatment.
OR
Patients with diagnosis of re-lapsed/refractoryMDS/AML with 10-19% bone mar-row blasts at initial diagnosis and ≥5%bone marrow blasts, and/or ≥1% peripheral blood blasts at screen-ing defined according to 2022 ICC criteria1 after at least one prior line of treatment who are ineligible for intensive salvage chemotherapy and/or allogeneic hematopoietic cell transplantation or who decline standard treatment.
3. IDH1-mutated as determined by a validated assay at a specific site (IDH1 R132).
4. ECOG 0-2.
5. Adequate hepatic function as evidenced by:
• Serum total bilirubin ≤ 3 × upper limit of normal (ULN) unless considered due to Gilbert’s syndrome, or leukemic involvement of the liver – following written approval by the Principal Investigator.
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT), ≤ 3.0 × ULN, unless considered due to leukemic involvement of the liver, following written approval by the Principal Investigator.
6. Adequate renal function as evidenced by creatinine clearance ≥ 30 mL/min based on the CKD-EPI formula for glomerular filtration rate (GFR).
7. Able to understand and willing to sign an informed consent form (ICF).
8. Written informed consent.
9. Female patient must either:
• Be of non-childbearing potential:
o Postmenopausal prior to screening defined as:
≥ 50 years and in postmenopausal state > 1 year or
< 50 years and in postmenopausal state > 1 year with serum FSH > 40 IU/l and serum estrogen < 30 ng/l or a negative estrogen test, both at screening
or
o Documented surgically sterile by bilateral tubal ligation or bilateral oophorectomy or status post-hysterectomy or uterine agenesis (at least 1 month prior to screening).
• If of childbearing potential:
o Agree not to try to become pregnant during the study and for 6 months after the final study drug administration
o And have a negative serum pregnancy test at screening
o And, if heterosexually active, agree to consistently use highly effective contraception per locally accepted standards in addition to a barrier method starting at screening and throughout the study period and for 6 months after the final study drug administration.
• Female patient must agree not to breastfeed starting at screening and throughout the study period, and for 2 months after the final study drug administration.
• Female patient must not donate ova starting at screening and throughout the study period, and for 6 months after the final study drug administration.
10. Male patient and their female partners who are of childbearing potential must be using highly effective contraception per locally accepted standards (see above *highly effective forms of birth control) in addition to a barrier method starting at screening and continue throughout the study period and for 4 months and 1 week after the final study drug administration.
11. Male patient must not donate sperm starting at screening and throughout the study period and for 4 months and 1 week after the final study drug administration.
12. Patient agrees not to participate in another interventional study while on treatment.
13. Ability to swallow and retain oral medication, no known malabsorption syndrome, adequate organ function.
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| E.4 | Principal exclusion criteria |
Patients eligible for inclusion in this study must not meet any of the following criteria:
1. Acute promyelocytic leukemia (APL) with t(15;17)(q22;q12); PML-RARA, or other translocations associated with APL.
2. AML with BCR-ABL translocation.
3. MDS with bone marrow blasts <10% at initial diagnosis (if patients progress from MDS to MDS/AML they should be treated with a hypomethylating agent first).
4. MDS with bone marrow blasts <5% at screening.
5. Prior treatment with ivosidenib, olutasidenib or a PHD inhibitor (e.g. roxadustat) within the last 6 months prior to screening (in the case of pre-treatment with ivosidenib, it is necessary to consult with the coordinating investiga-tor before patient inclusion).
6. Persistence of toxicity of prior chemotherapy above grade 1.
7. Treatment with any investigational agent within two weeks before day one of study treatment or less than 5 half-lives of the compound.
8. CNS disease or other severe acute or chronic medical or psychiatric condition, or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results, and in the judgment of the investigator would make the patient inappropriate for entry into this study.
9. Known allergy or suspected hypersensitivity to molidustat and/or ivosidenib and/or any exipients.
10. Taking medications with narrow therapeutic windows with potential interaction with investigational medication (see Appendix I), unless the patient can be transferred to other medications prior to enrolling or unless the medications can be properly monitored during the study.
11. Taking P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP) transporter- sensitive substrate medications (see Appendix J) unless the patient can be transferred to other medications within ≥ 5 half-lives prior to administration of molidustat and ivosidenib, or unless the medications can be properly monitored during the study.
12. Breast feeding at the start of study treatment.
13. Active infection, including hepatitis B or C or HIV infection that is uncontrolled at screening. An infection controlled with an approved or closely monitored antibiotic/antiviral/antifungal treatment is allowed.
14. Patients with a currently active second malignancy. Patients are not considered to have a currently active malignancy if they have completed therapy and are considered by their physician to be at < 30% risk of relapse within one year. However, patients with the following history/concurrent conditions are allowed:
• Basal or squamous cell carcinoma of the skin
• Carcinoma in situ of the cervix
• Carcinoma in situ of the breast
• Incidental histologic finding of prostate cancer
15. Significant active cardiac disease within 6 months prior to the start of study treatment, including New York Heart Association (NYHA) class III or IV congestive heart failure (Appendix H); myocardial infarction, unstable angina and/or stroke; or left ventricular ejection fraction (LVEF) < 40% by ultrasound obtained within 28 days prior to the start of study treatment.
16. Liver cirrhosis Child Pugh B or Child Pugh C or disorders of bilirubin metabolism, e.g. in patients with Crigler-Najjar syndrome or Rotor syndrome , with exception of Gilbert’s syndrome (see section 4.1 and 5.5).
17. QTc interval using Fridericia’s formula (QTcF) ≥ 480 msec or other factors that increase the risk of QT prolongation or arrhythmic events (e.g., heart failure, family history of long QT interval syndrome). Prolonged QTc interval associated with bundle branch block or pacemaking is permitted with written approval of the Coordinating Investigator.
18. Taking medications that are known to prolong the QT interval (see Appendix K), unless deemed critical and without a suitable alternative. In those cases, they may be administered with proper monitoring.
19. Dysphagia, short-gut syndrome, gastroparesis, or other conditions that limit the ingestion or gastrointestinal absorption of orally administered drugs.
20. Clinical symptoms suggestive of active central nervous system (CNS) leukemia or known CNS leukemia. Evaluation of cerebrospinal fluid (CSF) during screening is only required if there is a clinical suspicion of CNS involvement by leukemia during screening.
21. A known medical history of progressive multifocal leukoencephalopathy (PML).
22. Immediately life-threatening, severe complications of leukemia such as uncontrolled bleeding, pneumonia with hypoxia or shock, and/or severe disseminated intravascular coagulation.
23. Any other medical condition deemed by the Investigator to be likely to interfere with a patient’s ability to give informed consent or participate in the study.
24. Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint of phase Ia of the trial is the frequency of DLTs during cycle 1 of treatment (up to 42 days).
The primary endpoint of phase IIb of the trial is the rate of complete remission (CR), within the first 6 months of treatment as determined by the Investigator, based on the European LeukemiaNet (ELN2022) recommended response criteria. 6 ELN2022 response criteria will be also applied to MDS/AML patients. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Phase Ia of the trial: during cycle 1 of treatment (up to 42 days).
Phase IIb of the trial: within the first 6 months of treatment as determined by the Investigator |
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| E.5.2 | Secondary end point(s) |
Secondary Endpoints of this trial are:
(1)Combined rate of complete remission (CR), CR with partial hematologic recovery (CRh) and CR with incomplete hematologic recovery (CRi) within the first 6 months of treatment as determined by the Investigator, based on the European LeukemiaNet (ELN2022) recommended response criteria.
(2)Proportion of patients being transfusion-free for ≥ 8 weeks for erythrocytes and/or platelets during the first 24 weeks. This will be separately assessed for all patients and for patients who were transfusion dependent at screening.
(3)Event-free survival (EFS), defined as the time from C1D1 to failure to achieve CR or CRh or CRi within the first six months of treatment, death or relapse after achieving CR or CRh or CRi, whichever occurs first. A patient is said to have failed to achieve CR orCRh or CRi, if his/her best response after 6 months of treatment is less than CRh or CRi (e.g. morphologic leukemia free state, partial remission, stable disease, progressive disease) and is counted as an event on C1D1. If there is no bone marrow assessment documented at all, patients will be considered as non-responders with an event
on C1D1. Patients who are lost to follow up before C6D28 are censored on the date they were last known to be alive. Patients who die before C6D28 will be counted as non-responders with an event at C1D1. Patients who achieved CR/CRh/CRi and are not known to have relapsed or died will be censored at the date they were last known to be alive.
(4)Modified EFS, where failure of achieving CR/CRh/CRi during the first 6 months will be counted as an event on the date of last bone marrow assessment documented. If there is no bone marrow assessment documented at all, the time of the event will be C6D28. Patients lost to follow up before C6D28 will be censored on the date they were last known to be alive. Patients who die before C6D28 will be counted as an event at date
of death.
(5) Overall survival (OS), defined as the time from date of C1D1 to date of death due to any cause. Patients still alive or lost to follow up will be censored at the time they were last known to be alive.
(6) Relapse-free survival (RFS), defined as the time from date of achievement of CR alone, CR/CRh or CR/CRh/CRi until the date of relapse or death, whichever occurs first. Patients not known to have relapsed or died will be censored on the date they were last known to be alive.
(7) Cumulative incidence of relapse (CIR) after CR/CRh/CRi, as measured from the date of achievement of CR/CRh/CRi until the date of relapse. Patients not known to have relapsed will be censored on the date of last clinical assessment. Patients who died without relapse will be counted as a competing cause of failure.
(8) Cumulative incidence of death (CID) after CR/CRh/CRi, as measured from the date of achievement of CR/CRh/CRi until the date of death from any cause. Patients not known to have died will be censored on the date they were last known to be alive. Patients who experienced relapse in CR/CRh/CRi will be counted as competing cause of failure.
(9) CR/CRh/CRi without minimal residual disease (CR/CRh/CRiMRD−) rate at C2D1, C4D1,C7D1 and EOT (by molecular MRD assessment).
(10)Proportion of patients with ≥4-fold increase of erythropoietin (EPO) over baseline and of ≥8-fold decrease of R-2HG concentration in serum on C1D8, C2D1, C4D1 and C7D1.
Safety assessment will be done by using the following criteria:
(11) Frequency and severity of (severe) adverse events according to CTCAE version 5.0 (Appendix G).
(12) Proportion of patients requiring phlebotomy (hematocrit ≥ 45%)
(13) Day 30 and 60 mortality rates
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
(1) within 6 month of treatment
(2) during the first 24 weeks
(3) from C1D1 to failure to achieve CR or CRi within the first six months of treatment, death or relapse after achieving CR or CRi
(4) during the first 6 months
(5) during study period (time from date of C1D1 to date of death)
(6) during study period
(7) during study period (from C1D1 up to FU)
(8) during study period
(9) at C2D1, C4D1, C7D1 and EOT
(10) on C1D8, C2D1, C4D1 and C7D1
(11) from start of treatment until FU
(12) from start of treatment until FU
(13) Day 30 and 60 |
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| 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 | No |
| 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 | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| Dose escalation, combination therapy |
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| 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.8.3 |
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 | 14 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 48 |
| E.8.9.1 | In the Member State concerned days | |
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