Myeloid Neoplasms

o Fit for Intensive Therapy: Tx FLAG-Ida + Ziftomenib
 Inclusion criteria:
• Age: >18 - <75 years old
• R/R AML >5% BM blasts or blasts in blood x 2 >1 week apart
• Confirmed NPM1-mut or KMT2A-r
• ECOG <2
• Adequate organ function: AST/ALT <3xULN, T. bili <1.5 ULN, EF >50%, CrCl >50ml/min
 Exclusion criteria:
• Active CNS disease
• Uncontrolled infection
• QTcF >480ms
• RT/chemo/immune/anti-cancer therapy <14 days or 5 1/2T prior to first dose of study Rx
• HSCT w/o count recovery
• Active GvHD


o Unfit for Intensive Therapy: Tx LDAC + Ziftomenib
 Eligibility:
• Age >18 years old
• R/R AML >5% BM blasts or blasts in blood x 2 >1 week apart
• Confirmed NPM1 mutation or KMT2A rearrangement
• ECOG <2
• Adequate organ function: AST/ALT <3xULN, T. bili <1.5 ULN, EF >40%, CrCl >50ml/min
 Exclusion criteria:
• Active CNS disease
• Uncontrolled infection
• QTcF >480ms
• RT/chemo/immune/anti-cancer therapy <14 days or 5 1/2T prior to first dose of study Rx
• HSCT w/o count recovery
• Active GvHD


o KMT2A/NPM1 with FLT3 mutation: Tx Gilteritinib + Ziftomenib
 Eligibility:
• Age >18 years old
• R/R AML >5% BM blasts or blasts in blood x 2 >1 week apart
• Confirmed NPM1 mutation or KMT2A rearrangement
• Confirmed FLT3-ITD/TKD
• Prior Gilteritinib failure or intolerance
• ECOG <2
• Adequate organ function: AST/ALT <3xULN, T. bili <1.5 ULN, EF >40%, CrCl >50ml/min
 Exclusion criteria:
• Active CNS disease
• Uncontrolled infection
• QTcF >480ms
• RT/chemo/immune/anti-cancer therapy <14 days or 5 1/2T prior to first dose of study Rx
• HSCT w/o count recovery
• Active GvHD

Phase I to evaluate the safety, tolerability, and DLTs and determine the MTD and/or RDE(s) of INCA033989 in participants with MF or ET

Inclusion
- CALR mutated ET and MF
- MF or higher risk ET
- Existing documentation from a qualified local laboratory of CALR exon-9 mutation.
- Participants with MF or ET as defined in the protocol.

Exclusion:
- Presence of any hematological malignancy other than ET, PMF, or post-ET MF.
- Prior history of major bleeding, or thrombosis within the last 3 months prior to study enrollment.
- Has undergone any prior allogenic or autologous stem-cell transplantation or such transplantation is planned.
- Active invasive malignancy over the previous 2 years.
- History of clinically significant or uncontrolled cardiac disease.


Please send referrals to the following pool: P VICC Research Referrals/Eligibility

Phase I to evaluate the safety, tolerability, and DLTs and determine the MTD and/or RDE(s) of INCA033989 in participants with MF or ET

Inclusion
- CALR mutated ET and MF
- MF or higher risk ET
- Existing documentation from a qualified local laboratory of CALR exon-9 mutation.
- Participants with MF or ET as defined in the protocol.

Exclusion:
- Presence of any hematological malignancy other than ET, PMF, or post-ET MF.
- Prior history of major bleeding, or thrombosis within the last 3 months prior to study enrollment.
- Has undergone any prior allogenic or autologous stem-cell transplantation or such transplantation is planned.
- Active invasive malignancy over the previous 2 years.
- History of clinically significant or uncontrolled cardiac disease.


Please send referrals to the following pool: P VICC Research Referrals/Eligibility

Inclusion
-Must have morphologically confirmed diagnosis of MDS/MPN, excluding JMML, in accordance with WHO (2016) diagnostic criteria.
-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.
- 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 stable disease 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 adverse event 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 may occur provided that dose modifications are made as appropriate.

Exclusion:
-Known hypersensitivity to decitabine.
-Transformation to acute myeloid leukemia (e.g. >20% myeloid blasts in bone marrow or >20% circulating blasts in peripheral blood).
-Organ transplant recipients including allogeneic hematopoietic stem cell transplant (HSCT).
-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 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.

Please send referrals to the following pool: P VICC Research Referrals/Eligibility

Key inclusion criteria:
- Participants with histological confirmation of advanced hematologic malignancy including:
a. R/R AML, as defined by standardized criteria (e.g., European LeukemiaNet criteria [Dohner 2022]; after standard of care therapy. Participants with persistent leukemia after initial therapy or with recurrence of leukemia at any time after achieving a response during or after the course of treatment (including HSCT) are eligible.
b. R/R HR-MDS or very high risk MDS as per the Revised International Prognostic Scoring System (IPSS-R; Greenberg 2012) or Molecular International Prognostic Scoring System (IPPS-M, Bernard 2022) who are resistant or refractory to 4-6 cycles of hypomethylating agents (HMA; decitabine or azacitidine).
c. R/R CMML who are resistant or refractory to 4-6 cycles of hypomethylating agents (HMA; decitabine or azacitidine)

- White blood cells must be below 25,000/µL at time of enrollment. Participants may receive cytoreduction prior to enrollment.

- Historical documented evidence of HLA-A*02:01 allele positivity

-ECOG 0-1

Key exclusion criteria:
- Previous CTSG targeted therapy or treatment with any pMHC T-cell engager

- Isolated extramedullary relapse.

- Active central nervous system (CNS) disease.

Inclusion
-Must have morphologically confirmed diagnosis of MDS/MPN, excluding JMML, in accordance with WHO (2016) diagnostic criteria.
-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.
- 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 stable disease 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 adverse event 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 may occur provided that dose modifications are made as appropriate.

Exclusion:
-Known hypersensitivity to decitabine.
-Transformation to acute myeloid leukemia (e.g. >20% myeloid blasts in bone marrow or >20% circulating blasts in peripheral blood).
-Organ transplant recipients including allogeneic hematopoietic stem cell transplant (HSCT).
-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 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.

Please send referrals to the following pool: P VICC Research Referrals/Eligibility

Key inclusion criteria:
- Participants with histological confirmation of advanced hematologic malignancy including:
a. R/R AML, as defined by standardized criteria (e.g., European LeukemiaNet criteria [Dohner 2022]; after standard of care therapy. Participants with persistent leukemia after initial therapy or with recurrence of leukemia at any time after achieving a response during or after the course of treatment (including HSCT) are eligible.
b. R/R HR-MDS or very high risk MDS as per the Revised International Prognostic Scoring System (IPSS-R; Greenberg 2012) or Molecular International Prognostic Scoring System (IPPS-M, Bernard 2022) who are resistant or refractory to 4-6 cycles of hypomethylating agents (HMA; decitabine or azacitidine).
c. R/R CMML who are resistant or refractory to 4-6 cycles of hypomethylating agents (HMA; decitabine or azacitidine)

- White blood cells must be below 25,000/µL at time of enrollment. Participants may receive cytoreduction prior to enrollment.

- Historical documented evidence of HLA-A*02:01 allele positivity

-ECOG 0-1

Key exclusion criteria:
- Previous CTSG targeted therapy or treatment with any pMHC T-cell engager

- Isolated extramedullary relapse.

- Active central nervous system (CNS) disease.