This global, multicenter, Phase 2 (Part A)/3 (Part B) randomized, controlled, open-label study will evaluate the safety and efficacy of KRT-232 versus BAT for the treatment PMF, post PV MF, or post ET MF in subjects who are relapsed or refractory to JAK inhibitor treatment

Phase 1

• Conditions: Primary Or Secondary (Post-PV MF or Post-ET-MF) Myelofibrosis (MF) With Intermediate Or High-Risk TP53 Wild-Type (TP53 WT) Who Are Relapsed Or Refractory to Janus Kinase (JAK) - Inhibitor Treatment.; MedDRA version: 20.0Level: PTClassification code 10077161Term: Primary myelofibrosisSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 21.0Level: LLTClassification code 10074689Term: Post polycythemia vera myelofibrosisSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 21.0Level: LLTClassification code 10074690Term: Post essential thrombocythemia myelofibrosisSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); Therapeutic area: Diseases [C] - Cancer [C04]

• Registration Number: EUCTR2018-001671-21-HR
• Lead Sponsor: Kartos Therapeutics, Inc.

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2021-11-30
• Last Update Posted: 6 December 2021

Recruitment & Eligibility

• Status: Authorised-recruitment may be ongoing or finished
• Sex: All
• Target Recruitment: 385

Inclusion Criteria

Part A:
1. Adults >18 years of age
2. Palpable spleen measuring = 5 cm below the left lower costal margin or spleen volume of = 450 cm3 by MRI or CT scan assessment
3. Confirmed diagnosis of PMF, post–PV-MF, or post–ET-MF according to the World Health Organization (WHO) criteria
4. High-risk, intermediate-2 risk, or intermediate-1 risk, defined by Dynamic International Prognostic System (DIPSS)
5. ECOG performance status of 0 to 2
6. Adequate hematological, hepatic, and renal organ function (as per protocol definition and within 28 days prior to the first dose of KRT-232)
7. Female subjects of childbearing potential and their male partners, or male subjects who have female partners of childbearing potential must both use an effective contraception method during the study. In addition, male subjects must continue to use contraception for 3 months and 1 week after the last dose of study drug and female subjects must continue to use contraception for 1 month and 1 week after the last dose of study drug. Effective birth control for males includes either vasectomy or use of condoms. Effective birth control for females 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; and (f) 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.
Subjects in Part A must meet the following JAK inhibitor treatment failure criteria in order to be eligible for the study:
JAK Inhibitor treatment failure in Part A must meet either criterion (a) or (b) below:
a) Either a lack of spleen response defined as receiving at least 12 weeks of JAK inhibitor treatment and having both of the following:
• Persistent splenomegaly, by physical exam, that is palpable = 5 cm below the LLCM
• and TSS of >10 on the MPN-SAF TSS v.2.0 or patients with a single symptom score of >5 or two symptoms of >3, including only the
symptoms of left upper quadrant pain, bone pain, itching, or night sweats
b) Or progressive disease any time while on JAK inhibitor treatment as defined by any one of the following:
• Spleen volume increase by = 25% from the nadir as assessed by MRI or CT
• Appearance of new splenomegaly that is palpable at least 5 cm below the LCM
• A = 100% increase in palpable distance, below the LCM, for baseline splenomegaly of 5 to 10 cm
• A = 50% increase in palpable distance, below the LCM, for baseline splenomegaly of > 10 cm
Part B:
1. Adults >18 years of age
2. Confirmed diagnosis of PMF, post PV MF, or post ET MF, as assessed by treating physician according to the World Health Organization (WHO) criteria (Appendix 3)
3. High-risk, intermediate-2 risk, or intermediate-1 risk, defined by Dynamic International Prognostic System (DIPSS) (Appendix 4)
4. Subjects with p53WT MF by central laboratory testing
5. Relapsed or refractory to prior treatment with an approved JAK inhibitor defined as:
Relapsed subjects are those with progressive disease after JAK inhibitor treatment, defined by one of the following:
• Increase in spleen volume by =25% by radiographic imaging from nadir
• =100% increase in palpable distance below LLCM for baseline splenomegaly

Exclusion Criteria

Part A:
1. Patients who are positive for p53 mutations
2. Participation in another interventional clinical trial within the past 4 weeks of the first dose of KRT-232 (participation in observational studies is permitted)
3. Major surgery within the first 28 days of KRT-232
4. Chemotherapy, immunomodulatory drug therapy within 14 days prior to first dose of KRT-232
5. Prior splenectomy
6. Splenic irradiation within 3 months prior to the first dose of KRT-232
7. Prior allogeneic stem-cell transplantation or eligible for allogeneic stem cell transplantation
8. Previous treatment with histone deacetylase (HDAC) inhibitors or BCL-2 inhibitors
9. Prior MDM2 inhibitor therapy or p53-directed therapy
10. Women who are pregnant or breastfeeding
11. History of major organ transplant
12. Uncontrolled intercurrent illness including, but not limited to, acute hepatitis A; 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; ventricular arrhythmia; or psychiatric illness/social situations that would limit compliance with study requirements
13. Subjects with clinically significant bacterial, fungal, parasitic, or viral infection that requires therapy. Subjects with acute bacterial infections requiring antibiotic use should delay screening/enrollment until the course of antibiotic therapy has been completed.
14. 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
15. Grade 2 or higher QTc prolongation (>480 milliseconds per NCICTCAE criteria, version 5.0)
16. Growth factor treatment (e.g., erythropoeitin) within 14 days prior to first dose of KRT-232; no darbepoetin within 28 days prior to first dose of KRT-232
17. Active or chronic bleeding within 4 weeks prior to the first dose of KRT-232
Part B:
1. Prior MDM2 inhibitor therapy or p53-directed therapy
2. Participation in an interventional clinical trial within 28 days before randomization (participation in observational studies is permitted)
3. Major surgery or radiotherapy within 21 days prior to randomization, or anticipation of needing such procedures while receiving study treatment
4. JAK-, PI3k-, SYK-, BTK-, BET- or MTOR inhibitor treatment within 28 days prior to the Screening MRI/CT scan
5. Treatment with any other anticancer agent including chemotherapy, immunotherapy or biologic therapy within 28 days prior to randomization. Hydroxyurea may be taken within 1 day prior to Cycle 1 Day 1
6. Prior splenectomy
7. Splenic irradiation within 12 weeks of randomization.
8. Prior allogeneic stem-cell transplantation or plans for allogeneic stem cell transplantation
9. Women who are pregnant, lactating, breastfeeding or intending to become pregnant during the study.
10. History of major organ transplant
11. Active serious viral, mycobacterial, parasitic, fungal, and bacterial infections, including acute hepatitis A, herpes zoster, and progressive multifocal leukoencephalopathy (PML). Active serious infections must be resolved before randomization. Patients with acute infections requiring systemic antibiotic use should complete antibiotic therapy at

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified