To Investigate whether the combination of molidustat and an IDH1 inhibitor (ivosidenib) effectively inhibits leukaemia cells in patients with IDH1 mutated acute myeloid leukaemia (AML) or patients with IDH1 mutated myelodysplastic syndrome (MDS)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Medizinische Hochschule Hannover

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04], Diseases [C] - Hemic and Lymphatic Diseases [C15]

Trial duration

10 Jul 2023 → ongoing

Decision date (initial)

2024-11-06

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Servier · Bayer · German Cancer Aid

External identifiers

EU CT number

2024-514051-15-00

EudraCT number

2021-006895-17

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Safety, Dose response, Efficacy

• 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
complete remission (CR) rate of the combination treatment including molidustat and ivosidenib.

Secondary objectives 8

1. To assess the combined rate of CR, CR with partial hematologic recovery (CRh) and CR with incomplete hematologic recovery (CRi)
2. To assess the proportion of patients becoming transfusion-independent
3. To evaluate event-free survival (EFS), overall survival (OS), relapse-free survival (RFS), cumulative incidence of relapse (CIR), and cumulative incidence of death (CID) after CR/CRh/CRi of the combination treatment including molidustat and ivosidenib.
4. To evaluate minimal residual disease (MRD) status at sequential time points throughout treatment and the CR/CRh/CRiMRD− rate of the combination of molidustat and ivosidenib using molecular techniques (IDH1 mutation and other molecular markers).
5. To evaluate limited pharmacodynamics (PD) of molidustat (erythropoietin induction) and ivosidenib (R-2HG inhibition).
6. To assess safety and tolerability comparing the frequency and severity of (serious) ad-verse events according to CTCAE criteria.
7. To evaluate the proportion of patients requiring phlebotomy (hematocrit ≥ 45%)
8. To evaluate 30 and 60 day mortality rates

Conditions and MedDRA coding

Adult patients with relapsed or refractory IDH1-mutated AML or relapsed or refractory MDS/AML, who are not eligible for intensive chemotherapy including alloHCT

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 13

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 extramedullary disease) 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. OR Patients with diagnosis of relapsed/refractoryMDS/AML with 10-19% bone marrow blasts at initial diagnosis and ≥5%bone marrow blasts, and/or ≥1% peripheral blood blasts at screening 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 coordinating 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 coordinating 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: ▪ Age ≥ 50 years and in postmenopausal state > 1 year or ▪ Age < 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 Patient is 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 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. * Highly effective forms of birth control include: i. Established intrauterine device (IUD) or intrauterine system (IUS). ii. Bilateral tubal occlusion. iii. Vasectomy (a vasectomy is a highly effective contraception method provided the absence of sperm has been confirmed. If not, an additional highly effective method of contraception should be used). iv. Male is sterile due to a bilateral orchiectomy. v. Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual activity during the entire period of risk associated with the study drug. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical study and the preferred and usual lifestyle of the patient. * List is not all inclusive. Prior to enrollment, the investigator is responsible for confirming patient will utilize highly effective forms of birth control per the requirements of the CTFG Guidance document ‘Recommendations related to contraception and pregnancy testing in clinical trials’, September 2020 (and any updates thereof) during the protocol defined period. Since ivosidenib may decrease the concentrations of hormonal contraceptives, it is recommended to use alternative methods of contraception as mentioned above (see section 5.5). • 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 use 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 for the study treatment in the opinion of the investigator.

Exclusion criteria 24

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 investigator 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 excipients.
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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Phase Ia: Frequency of DLTs during cycle 1 of treatment (up to 42 days).
2. Phase IIb: Rate of complete remission (CR)within the first 6 months of treatment.

Secondary endpoints 13

1. Combined rate of complete remission (CR), CR with partial hematologic recovery (CRh) and incomplete hematologic recovery (CRi) within the first 6 months of treatment.
2. Proportion of patients being transfusion-free for ≥ 8 weeks for erythrocytes and/or platelets during the first 24 weeks.
3. Event-free survival (EFS)
4. Modified EFS
5. Overall survival (OS)
6. Relapse-free survival (RFS)
7. Cumulative incidence of relapse (CIR) after CR/CRh/CRi.
8. Cumulative incidence of death (CID) after CR/CRh/CRi.
9. CR/CRh/CRi without minimal residual disease (CR/CRh/CRiMRD−) rate at C2D1, C4D1 and C7D1 and EOT (by NGS).
10. Proportion of patients with ≥4-fold increase of erythropoietin (EPO) over screening and of ≥8-fold decrease of R-2HG concentration in serum on C1D8, C2D1, C4D1 and C7D1.
11. Frequency and severity of (serious) adverse events ac-cording to CTCAE version 5.0.
12. Proportion of patients requiring phlebotomy (hematocrit ≥ 45%).
13. Day 30 and 60 mortality rates.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Medizinische Hochschule Hannover

Sponsor organisation

Medizinische Hochschule Hannover

Address

Carl-Neuberg-Strasse 1, Gross Buchholz Gross Buchholz

City

Hanover

Postcode

30625

Country

Germany

Scientific contact point

Organisation

Medizinische Hochschule Hannover

Contact name

Hämatologische Studienzentrale

Public contact point

Organisation

Medizinische Hochschule Hannover

Contact name

Hämatologische Studienzentrale

Third parties 1

Locations

1 EU/EEA country · 16 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Temporary halts 1 · Art. 38 CTR

Urgent safety measures 1 · Art. 54 CTR

Unexpected events 1 · Art. 53 CTR

Note: SUSARs are reported via EudraVigilance, not CTIS — events shown here are CTIS-public notifications only.

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 6 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications