IRB Study Number 23-1258
Status Recruiting
Institute Taussig Cancer Institute
Description
Primary Objective
To evaluate the safety, tolerability, and DLTs and determine the MTD and/or RDE(s) of INCA033989 in participants with MF or ET.
Secondary Objectives
To evaluate the preliminary activity of INCA033989 in participants with MF.
To evaluate the preliminary activity of INCA033989 in participants with ET.
To evaluate changes in allele burden level of CALR exon-9 mutation in participants with MF or ET.
To evaluate the PK of INCA033989 in participants with MF or ET.
Inclusion Criteria
Ability to comprehend and willingness to sign a written ICF for the study.
Aged 18 years or older at the time of signing the ICF.
ECOG performance status score of the following:
• 0 or 1 for the dose-escalation part (Part 1a).
• 0, 1, or 2 for the dose-expansion part (Part 1b).
Life expectancy is greater than 6 months.
Willingness to undergo a pretreatment and regular on-study BM biopsies and aspirates (as appropriate to disease).
Willingness to avoid pregnancy or fathering children based on the criteria below:
a. Male participants with reproductive potential must agree to take appropriate precautions to avoid fathering children from screening through 90 days (a spermatogenesis cycle) after the last dose of study treatment and must refrain from donating sperm during this period. Permitted methods in preventing pregnancy (see Appendix A) should be communicated to the participants and their understanding confirmed.
b. Female participants who are WOCBP must have a negative serum pregnancy test at screening and a negative urine pregnancy test before the first dose on Day 1 and must agree to take appropriate precautions to avoid pregnancy from screening through the last safety follow-up visit and must refrain from donating oocytes during this period. Highly effective contraception methods (failure rate of < 1% per year) must be used (see Appendix A) and should be communicated to the participants and their understanding confirmed.
c. Female participants not considered to be of childbearing potential as defined in Appendix A are eligible.
- Existing documentation from a qualified local laboratory of CALR exon-9 mutation (preferably obtained by next-generation targeted sequencing or PCR).
For participants with MF:
Histologically confirmed diagnosis of PMF or post-ET MF according to the 2022 WHO criteria (see Appendix B).
Participants with MF who have been previously treated with JAK inhibitors for ≥ 12 weeks and are resistant, refractory, or intolerant to, or lost response to JAK inhibitor treatment or have intermediate- or high-risk DIPSS MF and are ineligible for JAK inhibitor treatment.
Myeloblast count < 10% in the BM (or in the peripheral blood if BM is not evaluable)
Evidence of evaluable residual burden of disease:
• Radiologic confirmation of splenomegaly (spleen volume ≥ 450 mL per MRI or CT). or
• Palpable spleen of > 5 cm below the left subcostal margin on physical examination at the screening visit.
For participants with ET:
Confirmed diagnosis of ET according to the 2022 WHO criteria (see Appendix B).
High risk, defined as follows:
• Age > 60 years or older at the time of signing the ICF or
• History of thrombosis (arterial or venous) or
• History of major bleeding (related to the underlying ET disease) or
• Bleeding risk, defined as platelet count > 1.5 × 1012/L or platelet count > 1 × 1012/L with documented von Willebrand disease
Documented resistance/intolerance to at least 1 line of prior cytoreductive therapy as determined by the investigator (including but not limited to hydroxyurea, interferon, thalidomide, busulfan, lenalidomide, or anagrelide) (Barosi et al 2007).
Platelet count > 450 × 109/L.
Exclusion Criteria
Presence of any hematological malignancy other than ET, PMF, or post-ET MF.
History or presence of an abnormal ECG that, in the investigator's opinion, is clinically meaningful. If screening QTcF interval is > 480 milliseconds, the ECG should be repeated twice and the mean QTcF of the 3 ECGs should be ≤ 480 milliseconds; if QTcF > 480 milliseconds, the participant is excluded. For participants with an intraventricular conduction delay (QRS interval > 120 milliseconds), the JTc interval may be used in place of the QTcF with sponsor approval. The JTc must be ≤ 340 milliseconds if JTc is used in place of the QTcF. Participants with left bundle branch block are excluded. Participants with QTcF prolongation due to a pacemaker may be enrolled with prior approval from the sponsor's medical monitor.
Prior history of major bleeding, or thrombosis within the last 3 months prior to study enrollment.
Participants with laboratory values at screening as defined in Table 6.
Unwillingness to be transfused with blood components including RBC packs and platelet transfusions.
Has undergone any prior allogenic or autologous stem-cell transplantation or such transplantation is planned.
Active invasive malignancy over the previous 2 years. Note: Participants with the following may be eligible to participate at the investigator's discretion:
• Early-stage basal cell or squamous cell skin cancer
• Completely resected intraepithelial carcinoma of the cervix
• Completely resected papillary thyroid and follicular thyroid cancers
Participants with malignancies with indolent behavior, such as prostate cancer treated with radiation or surgery, may be enrolled as long as they have a reasonable expectation to have been cured with the treatment modality received.
History of clinically significant or uncontrolled cardiac disease, including recent (within the last 12 months) unstable angina or acute myocardial infarction, or New York Heart Association Class III or IV congestive heart failure, or clinically significant arrhythmias not controlled by medication. Participants with a pacemaker and well-controlled rhythm for at least 1 month before the first dose of study treatment will be allowed.
Any major surgery within 28 days before the first dose of study treatment.
Active HBV (or at risk of reactivation), defined as follows: positive HBsAg result (laboratory test required at screening), and/or positive total anti-HBc result (laboratory test required at screening), and/or quantitative HBV DNA test result greater than the lower limits of detection of the assay (if known; laboratory test not required for eligibility purpose, but can be done as part of screening if available locally). Note: Participants with no prior history of HBV infection who have been vaccinated against HBV and who have a positive anti-HBs as the only evidence of prior exposure may participate in the study.
Active HCV, defined as follows: positive anti-HCV result (laboratory test required at screening) and quantitative HCV RNA test result greater than the lower limits of detection of the assay (laboratory test only required if anti-HCV–positive, can be done as part of screening if available locally). Note: Anti-HCV–positive participants who received and completed treatment for HCV that was intended to eradicate the virus may participate if HCV RNA levels are undetectable at least 12 weeks after the last dose of therapy. Anti-HCV–positive participants with no available confirmatory negative HCV RNA test results will be excluded.
Known history of HIV (1/2 antibodies).
Any condition or circumstance that would, in the investigator's judgment, interfere with full participation in the study (eg, unable, unlikely, or unwilling to comply with the dose schedule and study evaluations, active alcohol or drug addiction), including administration of study treatment and attending required study visits; pose a significant risk to the participant; or interfere with interpretation of study data.
Women who are pregnant or breastfeeding. Women must also refrain from breastfeeding during the course of study and for 30 days after the last dose of study treatment.
Presence of chronic or current active infectious disease requiring systemic antibiotic, antifungal, or antiviral treatment. Participants with acute infection requiring antibiotic, antifungal, or antiviral treatment use should delay screening/enrollment until the course of antibiotic antifungal, or antiviral therapy has been completed and the infection is not active anymore. Note: If a participant has a positive screening test result for SARS-CoV-2 infection, they should be excluded until test normalization and clinical recovery.
Any prior chemotherapy, immunomodulatory drug therapy, immunosuppressive therapy, biological therapy, endocrine therapy, targeted therapy, antibody, or hypomethylating agent used to treat the participant's disease (see Section 6.7) within 5 half-lives or 28 days (whichever is shorter) before the first dose of study treatment.
Any prior radiation therapy within 28 days before the first dose of study treatment. Palliative radiation therapy to single sites or small fields is allowed with at least a 1-week washout period before the first dose of study treatment.
Known hypersensitivity, severe reaction, or any known contraindications to the use of any of the active substances or excipients in the INCA033989 drug product.
Has any unresolved toxicity ≥ Grade 2 from previous therapy except for stable chronic toxicities (Grade 2) not expected to resolve, such as stable Grade 2 peripheral neuropathy.
Undergoing treatment with another investigational medication or has been treated with an investigational medication within 28 days before the first dose of study treatment.
Current use of prohibited medication described in Section 6.7.3.
Participants undergoing treatment with G-CSF or GM-CSF, romiplostim, or eltrombopag at any time within 4 weeks before the first dose of study treatment.
