| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsed or refractory AML, AML secondary to myeloproliferative neoplasms (MPN), and JAK2 mutationpositive AML. |
|
| 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 rates of complete remission (CR) and complete remission with partial hematological improvement (CRh). |
|
| E.2.2 | Secondary objectives of the trial |
(Secondary Obj. Part A/Part B): Part A Only-to determine rates complete remission (CR), complete remission w/partial hematological improvement (CRh). To determine Overall Response Rate.To determine rate of return chronic phase MPN w/peripheral blast count <10%. To determine prop. subjects transition to allogeneic stem cell transplant. To determine efficacy JAK2 mutational status. To determine Duration of Response. To determine Progression-Free Survival. To determine Overall Survival. To determine efficacy KRT-232 in CR and CRh subjects w/treatment-naïve blast-phase AML vs. subjects w/ blast-phase AML which has been previously treated. Safety and tolerability of KRT-232. To monitor PK of KRT-232 and metabolites.
(Exploratory Obj.): To evaluate the combination relative to select PK,PD,disease markers,markers of resistance in subjects who respond and in those who relapse on therapy.To determine UGT1A1*28 genotype, compare KRT-232 and KRT-232 glucuronide plasma conc. across genotypes. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Adults ≥ 18 years of age
2. ECOG performance status of 0 to 2
3. Part A: 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 FLT3 inhibitor (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 IDH2 inhibitors are approved and available in the country in which the patient is to be treated.
4. Part B: Patients with AML secondary to MPN,as defined by ≥20% blasts in the bone marrow or peripheral blood,or JAK2 mutation positive AML.
5. Part B: Patients may have been treated with 0 to 2 prior lines of therapy for their AML. 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 IDH1 or 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 28 days prior to the first dose of KRT-232.
Hepatic: Direct bilirubin ≤2.0 times the upper limit of normal (ULN), unless Gilbert’s
Syndrome; 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. 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 week after the last dose of study drug 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. |
|
| E.4 | Principal exclusion criteria |
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. 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; or psychiatric illness/social situations that would limit compliance with study requirements
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) |
|
| 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: Responses will be assessed per the 2017 European LeukemiaNet (ELN) response criteria (Appendix 3). Blasts in the bone marrow will be defined morphologically by exam of the aspirate or biopsy (if aspirate not available). Blasts in the blood will be defined immunophenotypically. 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). |
|
| 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. Bone marrow aspirate and biopsy 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. |
|
| E.5.2 | Secondary end point(s) |
• Responses (in Part A and B) will be assessed per the 2017 European LeukemiaNet (ELN) response criteria (Appendix 3) to determine rates of complete remission (CR) and complete remission with partial hematological improvement (CRh) (in Part A); to determine the overall response rate (ORR); rate of return to chronic phase MPN with peripheral blast count <10%; duration of response (DoR); progression-free survival (PFS); overall survival (OS); efficacy of KRT-232 in CR and CRh subjects who have treatment-naïve blastphase AML vs. subjects who have blast-phase AML which has been previously treated. Blasts in the bone marrow will be defined morphologically by exam of the aspirate or biopsy (if aspirate not available). Blasts in the blood will be defined immunophenotypically. 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).
• Number of subjects who transition to allogeneic transplant
• Efficacy analyses will be evaluated in subjects who are JAK2 V617F positive and negative
• 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.
(Exploratory endpoints):
• Biomarkers including but not limited to:
-TP53 mutation status, JAK2 mutations, and other AML-, sAML-, and MPN-related genes
-TP53-related gene expression: p21 (CDKN1A), MDM2, MDMX (MDM4), PUMA (BBC3)
-Flow cytometry of peripheral blood blasts
-MIC-1 protein in serum
• UGT1A1*28 genotype (*1*1, *1*28, *28*28) |
|
| 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. Bone marrow aspirate and biopsy 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
• Safety endpoints will be assessed at various timepoints as per the Schedule of Assessments (Appendix 1 of the Protocol).
• PK: At Cycle 1, Cycle 2, Day 1: Pre-dose and a single point taken anytime from 0.5 to 6 hours post-dose. At Cycle 1 Day 8: 24 hours (window ±1 hour) after the Day 7 dose
(Exploratory endpoints):
• Biomarkers and UGT1A1*28 genotype: blood sample collected and stored at the time points indicated in Table 4. |
|
| 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 | No |
| 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 | 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 |
| This is a Phase 1b/2 study with a dose-escalation phase (Part A) and an expansion phase (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 | No |
| 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 combined 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 | 3 |
| 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 | 6 |
| 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 |
| Austria |
| Belgium |
| Bulgaria |
| Canada |
| Czech Republic |
| Denmark |
| Finland |
| France |
| Germany |
| Hong Kong |
| Hungary |
| Ireland |
| Israel |
| Italy |
| Korea, Republic of |
| Norway |
| Poland |
| Romania |
| Russian Federation |
| Singapore |
| Spain |
| Sweden |
| Switzerland |
| Taiwan |
| United Kingdom |
| United States |
|
| 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 | 5 |
| 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 | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
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