| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Myelodysplastic syndrome/Myeloproliferative Neoplasm Overlap Syndromess |
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| E.1.1.1 | Medical condition in easily understood language |
| Myelodysplastic syndrome/Myeloproliferative Neoplasm Overlap Syndromes |
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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 | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10077465 |
| E.1.2 | Term | Myeloproliferative neoplasm |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| 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 |
Phase 1: To characterize the DLTs of each novel oral targeted agent in combination with oral ASTX727 in order to determine the recommended phase 2 dose (RP2D) and schedule.
Phase 2: To test whether the overall response to each novel ASTX727 combination therapy in MDS/MPN patients is sufficiently high to warrant further investigation in more definitive trials.
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| E.2.2 | Secondary objectives of the trial |
• To expand the safety analysis of each treatment combination in MDS/MPN patients.
• To assess the morphologic bone marrow response in MDS/MPN patients treated on each Arm of the study.
• To estimate the effect of each treatment combination on patient survival
• To test the applicability of the proposed MDS/MPN IWG response criteria across multiple Arms of this study.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Must be ≥ 18 years of age at the time of signing the ICF; must voluntarily sign an ICF; and must be willing and able to meet all study requirements.
2. Must have morphologically confirmed diagnosis of MDS/MPN, excluding JMML, in accordance with WHO (2016) diagnostic criteria.
3. Treatment-naïve patients (patients who have had no prior disease-modifying therapy) may enroll in any AM-001 Arm that is open to accrual in phase 1 or phase 2. Treatment-naïve patients may have received recombinant erythropoietin, danazol, hydroxyurea or anagrelide, which are not considered to be disease-modifying therapy for the purpose of this study.
4. After an appropriate wash-out period, patients who have failed (or were intolerant to) prior therapy with a regimen(s) containing a DNMTi may enroll in any Arm in phase 1b or any Arm which has met the criterion of the first Simon’s Stage and are open to accrual in the second Simon’s Stage in phase 2. Except in the first stage of the phase 2, there are no limits on number of prior therapies if the patient meets all other eligibility criteria. Previously treated patients include:
• Patients treated with DNMTi therapy prior to enrollment in AM-001 who failed to achieve a complete remission, per the MDS/MPN IWG response criteria, after at least 4 cycles of DNMTi therapy;
• Patients enrolled in AM-001, or patients treated off-study with a regimen containing a DNMTi, who have definitive disease progression as defined in the protocol after at least 2 cycles of the prior therapy—this includes patients who fail to achieve a response with clearly progressive disease and patients who achieve an initial response who then lose that response;
• Patients enrolled in AM-001 who have SD as best response at the second response evaluation after 6 cycles of the prior AM-001 therapy;
• Patients treated on AM-001 who had and recovered from an AE that precludes further therapy on that Arm; after recovery from a toxicity that is likely to be related to ASTX727, enrollment in another AM-001 Arm may occur provided that dose modifications are made as appropriate.
5. Must be willing to undergo bone marrow biopsy with aspiration during screening and bone marrow aspiration with tissue collection for disease assessment and
correlative studies periodically throughout the trial.
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2.
7. Life expectancy of at least 3 months, as assessed by the treating physician.
8. For previously treated patients, recovery to ≤ Grade 1 or baseline of any toxicities due to prior systemic treatments, excluding alopecia.
9. Must have adequate hepatic and renal function during screening as demonstrated by:
• ALT (SGPT) and AST (SGOT) ≤3x the institutional upper limit of normal (ULN);
• Total bilirubin ≤1.5x ULN or ≤2x ULN, if upon judgment of the treating investigator the elevated bilirubin is due to extramedullary hematopoiesis related to the underlying MDS/MPN or to Gilbert’s disease;
• Creatinine < 1.5x ULN or estimated creatinine clearance (eCCR) >/=40 ml/min/1.73m2. Patients must have eCCR >/= 60ml/min/1.73m2 to enter into the INCB59872 arm. eCCR may be calculated using the standard institutional formula. The estimation tool/formula employed and result must be declared in the CRF. |
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| E.4 | Principal exclusion criteria |
1. Patients should be excluded from any treatment Arm that includes a novel targeted agent to which they have had previous exposure. Novel targeted agents in this study include itacitinib (INCB039110) only, currently. Patients who have had prior exposure to ASTX727 therapy are not excluded, provided they meet all other eligibility criteria.
2. Prior receipt of any investigational study drug, including treatment on any prior AM-001 Arm, within 30 days or 5 half-lives (whichever is shorter) before receiving the first dose of study drug in an Arm of AM-001, except if approved by the medical monitor.
Prior receipt of any systemic antineoplastic therapy, including but not limited to prior DNMTi therapy, standard induction or cytotoxic chemotherapy (excluding hydroxyurea), or approved targeted agent within 21 days or 5 half-lives (whichever is shorter) before receiving the first dose of study drug in an Arm of AM-001.
4. Known hypersensitivity to decitabine.
5. Transformation to acute myeloid leukemia (e.g. >20% myeloid blasts in bone marrow or >20% circulating blasts in peripheral blood).
6. Organ transplant recipients including allogeneic hematopoietic stem cell transplant.
7. History of clinically significant or uncontrolled cardiac disease, including recent history (within 6 months) of unstable angina, acute myocardial infarction, New York Heart Association Class III or IV congestive heart failure, or clinically significant uncontrolled arrhythmia. Patients with history of atrial tachycardia and/or bradycardia that is well-controlled with medical management and/or pacemaker for at least 1 month before the first dose of study drug will be allowed.
8. History of abnormal ECG or presence of abnormal screening ECG that, in the investigator’s opinion, is clinically significant and contraindicated for clinical study. Corrected QT interval (QTc), as corrected by Fredericia, on screening ECG >500 milliseconds is excluded, unless there is concomitant RBBB or concomitant LBBB with a pacemaker.
9. Any known contraindications to the use of ASTX727.
10. Any sign of active and clinically significant bleeding.
11. Other active malignancy, not including localized non-melanoma skin cancer, cervical carcinoma in situ, breast ductal carcinoma in situ, or localized prostate cancer controlled with hormone therapy. Patients with history of other cancers should be free of disease without ongoing anti-neoplastic therapy for at least 2 years.
12. Receipt of wide-field radiotherapy (including therapeutic radioisotopes) ≤ 28 days or limited field radiation for palliation ≤ 14 days prior to starting study medications; or has not recovered from side effects of such therapy.
13. Patients who require continuation of a prohibited concomitant medication for which no alternative therapy or allowable substitute is available.
14. Active, uncontrolled infection. Patients with infection that is under control with active treatment are eligible.
15. Major surgery requiring general anesthesia within 4 weeks prior to starting study treatment. (Placement of a central line or port-a-catheter is acceptable within this time frame and does not exclude the patient.)
16. Women who are pregnant or lactating.
17. Subjects who expect to conceive or father children within the projected duration of the study and/or who are unwilling to use highly effective methods of contraception throughout the duration of the study, starting with the screening visit through the end of treatment visit. For WOCBP, a negative urine pregnancy test at screening and immediately prior to initiating treatment on any AM-001 treatment Arm (Cycle 1 Day 1) is required.
18. Any concurrent serious or unstable medical or psychiatric condition that in the investigator’s opinion would jeopardize the patient’s ability to provide informed consent or to comply with the protocol.
19. Any psychological, familial, geographical or sociological condition that in the investigator’s opinion would jeopardize the patient’s ability to comply with the protocol.
20. Erwachsene mit MDS/MPN, die als schutzbedürftig gelten oder nicht in der Lage sind, eine freiwillige Einwilligung zu erteilen.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
• Phase 1: AE rates and RP2D and schedule
• Phase 2: Overall response rate. Overall response includes patients who achieve a best response of CR, PR, optimal or partial MR, or CB as defined by the modified MDS/MPN IWG proposed response criteria.
• Response will be assessed by physical examination, bone marrow biopsy and/or aspiration, MPN-SAF total symptom score (TSS), CT scan of the abdomen and hematologic laboratory parameters as per the modified MDS/MPN IWG response criteria.
• Scheduled assessments will occur on Cycle 3 Day 1, on Cycle 7 Day 1 and at the End of Treatment.
• Unscheduled response assessments may be performed as per routine clinical care and may be included in the best response determination |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
AEs: throughout the study
Overall response rate: Cycle 3 Day 1, on Cycle 7 Day 1 and at the End of Treatment.
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| E.5.2 | Secondary end point(s) |
• AE/DLT severity and frequency
• Safety and tolerability will be assessed by means of historical report, physical examinations and laboratory safety evaluations.
• CR/MR rate defined as the proportion of patients who achieve either complete remission or marrow response as a best response to treatment.
• Morphologic response will be assessed by bone marrow biopsy and/or aspiration and responses determined by the modified MDS/MPN IWG response criteria.
• Overall survival (OS) and progression-free survival (PFS); defined as the time from first protocol-indicated treatment to death for any reason (OS) or to disease progression or death for any reason (PFS).
• Survival follow up will be made approximately every 3 months after the EOT on any Arm to determine both overall and progression free survival |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
AEs: throughout the study
Overall survival (OS) and progression-free survival (PFS): time of death for any reason (OS) or disease progression or death for any reason (PFS). |
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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 | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| 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 |
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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.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 9 |
| 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 |
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| 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 | 3 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | |
| 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 | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 15 |
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