| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Relapsed or refractory Acute Myeloid Leukemia (AML), AML secondary to
myeloproliferative neoplasms (MPN) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Patients with Acute Myeloid Leukemia (AML). |
|
| 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 | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10000886 |
| E.1.2 | Term | Acute myeloid leukemia |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 |
Primary Objective for Part A: To determine KRT-232 recommended phase 2 dose (RP2D).
Primary Objective for Part B: To determine the RP2D of KRT-232. |
|
| E.2.2 | Secondary objectives of the trial |
Part A Only: To determine the rates of complete remission (CR) and complete remission with partial hematological improvement (CRh);
Part B Only: To determine the rates of complete remission (CR), CR with partial hematological improvement (CRh) and CR with incomplete hematologic recovery (CRi);
To determine the overall response rate (ORR), CRc and best overall response (BOR);
To determine the rate of return to chronic phase MPN with peripheral blast count <10%;
To determine proportion of subjects who transition to allogeneic stem cell transplant;
To determine duration of response (DOR) in Part A;
To determine DOR in Part B;
To determine progression-free survival (PFS);
To determine overall survival (OS);
Safety and tolerability of KRT-232;
To monitor pharmacokinetics (PK) of KRT-232 and metabolites. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Part A Inclusion Criteria
Part A subjects must meet all the following criteria to be eligible for the
study:
1. Adults ≥ 18 years of age
2. ECOG performance status of 0 to 2
3. Patients with relapsed or refractory AML, or treatment-naïve AML secondary to MPN. Diagnosis of AML must be according to World Health Organization (WHO) criteria with at least 20% blasts in the marrow and/or extramedullary leukemia. Patients with known fms-like tyrosine kinase 3 (FLT3) mutations must have been treated with a FLT3inhibitor (unless contraindicated) if FLT3 inhibitors are approved and available in the country in which the patient is to be treated. Patients who are known isocitrate dehydrogenase 1 (IDH1) or IDH2 mutation positive must have been previously treated with an IDH1 or IDH2 inhibitor, respectively, (unless contraindicated) if IDH1 or IDH2inhibitors are approved and
available in the country in which the patient is to be treated.
4. Adequate hepatic and renal function within 28 days prior to the first
dose of KRT-232 as described in the protocol.
5. Females of childbearing potential and males who have partners of childbearing potential must agree to use an effective contraception method during the study . In addition, males must continue to use contraception for 3 months and 1 we and females must continue to use contraception for 1 month and 1 week after the last dose of study drug.
Effective birth control includes (a) combined, estrogen and progestogen
containing, hormonal contraception (oral, intravaginal, transdermal); (b)
progestogen-only hormonal contraception (oral, injectable, implantable); (c) intrauterine device; (d)intrauterine hormone-releasing system; (e) bilateral tubal occlusion; (f) vasectomized partner; and (g) sexual abstinence when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods)and withdrawal are not acceptable methods of contraception.
Part B Inclusion Criteria
Part B subjects must meet all of the following criteria to be eligible for
the study:
1. Adults ≥ 18 years of age who are able to provide informed consent
2. ECOG performance status of 0 to 2
3. Patients with relapsed or refractory AML secondary to MPN (myelofibrosis [MF],polycythemia vera [PV], or essential thrombocythemia [ET]). Diagnosis of AML must be according to WHO criteria with at least 20% blasts in the marrow and/or extramedullary leukemia.
4. Patients with TP53 wild-type disease, based on local or central testing.
5. Patients may have been treated with ≥1 prior lines of therapy for their AML secondary to MPN. Patients with known FLT3 mutations must have been treated with a FLT3 inhibitor (unless contraindicated) if FLT3 inhibitors are approved and available in the country in which the patient is to be treated. Patients with relapsed or refractory disease who are known IDH1 or IDH2 mutation positive, must have been previously treated with an IDH1or IDH2 inhibitor (respectively) (unless contraindicated) if IDH1 or IDH2 inhibitors are approved and available in
the country in which the patient is be treated.
6. Adequate hepatic and renal function within 7 days prior to the first dose of KRT-232:
• Hepatic: Total bilirubin ≤2.0 times the upper limit of normal (ULN).
Subjects with known Gilbert's Syndrome or disease-related hemolysis must have a total bilirubin≤3.0 X ULN; aspartate transaminase/serum glutamic oxaloacetic transaminase(AST/SGOT) and alanine transaminase/serum glutamic pyruvic transaminase(ALT/SGPT) ≤2.5 ULN
• Renal: Estimated creatinine clearance ≥30 mL/min by Cockcroft Gault.
7. Female subjects of childbearing potential and their male partners, or male subjects who have female partners of childbearing potential must both use a highly effective contraception method during the study. In addition, after the last dose of study drug, female subjects must continue to use contraception for 1 month and 1 week and male subjects must continue to use contraception for 3 months and 1 week. A woman is considered of childbearing potential (i.e., fertile, following menarche and until becoming post-menopausal) unless permanently sterile. Note: Marketed drugs administered concomitantly in this study may have different contraception requirements, including required duration of contraception use. The contraception requirements in the local
prescribing guidelines must be followed for all concomitant drugs administered in this study. |
|
| E.4 | Principal exclusion criteria |
Part A Exclusion Criteria
Part A subjects who meet any of the following criteria will not be eligible
for the study:
1. Patients who are TP53 mutation positive
2. Participants who are either refractory to or relapsed within 90 days of receiving a regimen containing a cumulative dose of ≥ 18 g/m2 of cytarabine are not eligible to be treated with cytarabine on this study but may be treated with decitabine on this study
3. Patients who have received prior treatment with decitabine are not eligible to receive decitabine in this study but may be treated with cytarabine on this study
4. Patients who have received an allogeneic HSCT within 90 days of enrollment or who have active graft-versus-host disease requiring active therapy and have a donor
5. Patients who are eligible for an allogeneic HSCT per the opinion of the investigator and have a donor. Patients who are HSCT-eligible in the opinion of the investigator, but who refuse a transplant, are eligible for the study.
6. Patients who have received immunosuppressive therapy for graft-versus-host disease within 1 month prior to enrollment into this study
7. Patients with acute promyelocytic leukemia
8. Patients with a history of bleeding diathesis
9. Patients with known active CNS involvement with AML
10. Concurrent anticancer treatment, such as chemotherapy, cytoreductive therapy, immune therapy, or cytokine therapy within 14 days of the first dose of KRT-232, provided they have recovered from treatment toxicity. Patients on hydroxyurea may continue therapy with hydroxyurea until the day before starting therapy on this study. Patients on FLT3 inhibitors may continue therapy with FLT3 inhibitors until the day before starting therapy on this study. Subjects on JAK inhibitors should be tapered off JAK inhibitor therapy prior to starting treatment on this study per the JAK inhibitor tapering guidelines outlined in Section 7.4.1 of this protocol.
11. Patients previously treated with MDM2 antagonist therapies
12. Patients who have had major surgery within 28 days prior to the first treatment with KRT-232
13. Women who are pregnant or breastfeeding
14. Patients with uncontrolled intercurrent illness including, but not limited to, known active hepatitis A, B, or C; known history of human immunodeficiency virus (HIV)-positive; clinically significant cardiac disease (New York Heart Association Class III or IV); symptomatic congestive heart failure; unstable angina pectoris; unstable ventricular arrhythmia; patients with psychiatric illness/social situations that would limit compliance with study requirements; and patients who have been committed to an institution by judicial or administrative authority
15. Subjects with uncontrolled bacterial, fungal, parasitic, or viral infection. Subjects with acute bacterial infections requiring antibiotic use should not enroll until the infection is stable in the judgement of the treating physician; these patients may be on antibiotics at enrollment.
16. Other malignancy within the last 3 years, other than curatively treated basal cell or squamous cell skin cancer, carcinoma in situ of the cervix, organ-confined or treated nonmetastatic prostate cancer with normal prostate-specific antigen, in situ breast carcinoma after complete surgical resection, or superficial transitional cell bladder carcinoma
17. Grade 2 or higher QTc prolongation (>480 milliseconds per NCI-CTCAE criteria, version 5.0)
Part B Exclusion Criteria
Subjects who meet any of the following criteria will not be eligible for
Part B of the study:
1. Allogeneic stem cell transplant within 3 months; autologous stem cell transplant within 3 months or active graft-versus-host disease prior to first dose of study treatment
2. Patients who are eligible for an allogeneic HSCT per the opinion of the investigator and have a donor. Patients who are HSCT-eligible in the opinion of the investigator, but who refuse a transplant, are eligible for the study.
3. Patients who have received immunosuppressive therapy for graft-versus-host disease within 1 month prior to enrollment into this study
4. Patients with acute promyelocytic leukemia
5. Patients with a history of bleeding diathesis; major hemorrhage or intracranial hemorrhage within 24 weeks prior to the first dose of study
treatment
6. Patients with known active CNS involvement with AML
7. Concurrent anticancer treatment, such as chemotherapy, cytoreductive therapy, immune therapy, or cytokine therapy within 14 days of the first dose of KRT-232. Patients on hydroxyurea may continue therapy with hydroxyurea until the day before starting therapy on this study. Subjects on JAK inhibitors should be tapered off JAK inhibitor therapy prior to starting treatment on this study per the JAK inhibitor tapering guidelines outlined in Section 7.4.1 of this protocol.
Please refer to the protocol for full list of exclusion criteria. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
• Part A: Dose-limiting toxicities (DLTs) of KRT-232 in combination with cytarabine and DLTs of KRT-232 in combination with decitabine at each dose level.
• Part B: The safety review committee (SRC) will determine the RP2D
based on safety and tolerability data obtained from each arm. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
• DLTs are defined as the following study treatment-related adverse events (TEAEs) occurring
in the 1st cycle (i.e., in the first 28 days) of Part A.
• 2017 ELN response criteria will be used to assess the Bone marrow aspirate and biopsy results.
Part A: Bone marrow aspirate and/or biopsy, and peripheral blood, will be obtained at:: Screening; Within 4 days of the end of Cycles 1, 3, 6, 9, 12, 15, and 18; Thereafter, within 4 days of the end of every 6th cycle while on study treatment; At suspected disease progression.
Part B: Bone marrow aspirate and/or biopsy, and peripheral blood, will be obtained at: Screening; Within 4 days of the end of Cycle 1; Thereafter, within 4 days of the end of Cycle 3 and every 3 cycles thereafter while on study treatment; At suspected disease progression |
|
| E.5.2 | Secondary end point(s) |
Part A: Responses will be assessed per the Modified 2017 ELN response
criteria.
Blasts in the bone marrow will be defined morphologically by exam of
the aspirate and/or biopsy.
CRh is defined as <5% of blasts by morphology in the bone marrow, no evidence of disease (blasts in blood by flow cytometry) and at least partial recovery of peripheral blood counts (platelets >50,000/μL and ANC >500/μL).
Part B: Responses will be assessed per the Modified 2017 European Leukemia Net (ELN) response criteria. Blasts in the bone marrow will be defined morphologically by exam of the aspirate and/or biopsy.
• Overall response includes morphologic leukemia-free state (MLFS), CR, CRh, CRi and PR.
• Composite complete remission (CRc = CR + CRh) rate.
• The proportion of patients that return to chronic phase (peripheral blast count <10%).
• Number of subjects who transition to allogeneic transplant.
• Duration of response (DOR) is defined as the time from response initiation to PD/death in subjects who have achieved CR or CRh.
Subjects with MLFS by bone marrow aspirate and/or biopsy performed earlier in the course of therapy who convert to CRh or CR do not require a separate bone marrow aspirate and/or biopsy at time of CRh or CR to document this.
• Progression-free survival (PFS )is defined as the time from first dose date to PD per modified 2017 ELN response criteria or death due to any cause, whichever is sooner.
• Overall survival (OS) is defined as the time from first dose date to death due to any cause.
• Analyses of the safety endpoints will include the following measurements or assessments: physical examinations; laboratory tests; KRT-232 dose reductions, interruptions and discontinuations; adverse events (AEs), serious AEs (SAEs), electrocardiograms (ECGs), vital signs.
• KRT-232 and acyl glucuronide metabolite (M1) PK will be monitored on Cycles 1 and 2 with sparse sampling:
- Cycle 1, Cycle 2 on Day 1: Pre-dose and a single point taken anytime from 0.5 to 6 hr post-dose in Part A; pre-dose and 2 hours post-dose in Part B;
- Cycle 1 Day 8: 24 hours after the Day 7 dose. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
• 2017 ELN response criteria will be used to assess the Bone marrow
aspirate and biopsy results.
Part A: Bone marrow aspirate and/or biopsy, and peripheral blood, will
be obtained at:: Screening; Within 4 days of the end of Cycles 1, 3, 6, 9,
12, 15, and 18; Thereafter, within 4 days of the end of every 6th cycle
while on study treatment; At suspected disease progression.
Part B: Bone marrow aspirate and/or biopsy, and peripheral blood, will
be obtained at: Screening; Within 4 days of the end of Cycle 1;
Thereafter, within 4 days of the end of Cycle 3 and every 3 cycles
thereafter while on study treatment; At suspected disease progression
• Safety endpoints will be assessed at various timepoints as per the
Schedule of Assessments.
• PK: As defined in secondary end points. |
|
| 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 | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| 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 |
| Tolerability, Biomarker Assessments |
|
| 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 |
| Phase 1b/2 study with a dose-escalation phase (Part A) and multi-arm single agent KRT-232 (Part B) |
|
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
| KRT-232 alone and in combination with Low-Dose Cytarabine (LDAC) or Decitabine in AML patients. |
|
| 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 | 6 |
| 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 | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 50 |
| 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 |
| Israel |
| Korea, Republic of |
| United States |
| Belgium |
| France |
| Hungary |
| Poland |
| United Kingdom |
| Spain |
| Germany |
| Italy |
|
| 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
|
| The study will be considered complete 2 years after the last subject is enrolled, at which time subjects who remain on study treatment will be evaluated for eligibility to enroll in a rollover study. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
Print
