ABL001 + Dasatinib + Prednisone + Blinatumomab in BCR-ABL+ B-ALL or CML

Inclusion Criteria:

• Participants must meet the following criteria on screening examination to beeligible to participate in the study:

• Participants must have cytopathologically confirmed CD19+ BCR-ABL1+ acuteleukemia (B-cell ALL, mixed phenotype acute leukemia, or CML in lymphoid blastcrisis with ≥ 5% lymphoblasts.)22

• BCR-ABL1 positive status may be confirmed by FISH, karyotype analysis, ormolecular testing for p210 (b2a2 or b3a2) or p190 (e1a2) transcripts.

• Patients with asymptomatic central nervous system (CNS) disease areeligible and may be treated concurrently with intrathecal chemotherapy.

• Dose escalation: Participants must NOT be suitable for or willing to receivestandard intensive induction chemotherapy.

• Dose expansion: Participants aged 18 years and older will be eligibleregardless of suitability for intensive induction chemotherapy.

The following groups are not considered suitable for standard intensive induction chemotherapy:

• Participants who have not received standard intensive induction chemotherapy and areaged ≥ 50 years.

• Participants who have not received standard intensive induction chemotherapy and areaged 18 to 49 years and unfit due to co-morbidity or other factors to receiveintensive chemotherapy. Specific criteria that would suggest that a patient isunsuitable for intensive induction chemotherapy include:

• Severe cardiac comorbidity (congestive heart failure or documentedcardiomyopathy with EF ≤50%).

• Severe pulmonary comorbidity (documented pulmonary disease with DLCO ≤ 65% orFEV1 ≤ 65%, or dyspnea at rest, or requiring oxygen).

• ECOG performance status of 2 due to medical conditions unrelated to leukemia.

• Any other comorbidity that the physician judges to be incompatible withintensive cytotoxic chemotherapy.

• Participants aged ≥ 18 years with disease that is relapsed or refractory to 1 ormore cycles of standard intensive induction chemotherapy.

• ECOG performance status 0-3 (Appendix A). ECOG value of 3 is allowed afterdocumented discussion with PI, if poor performance status is attributed tounderlying disease.

• Participants must have normal organ function as defined below:

• Creatinine ≤ 1.5x institutional upper limit of normal.

• Amylase and lipase values ≤ 3.0x institutional upper limit of normal.

• Alkaline phosphatase ≤ 2.5x institutional upper limit of normal (unless consideredto be not of hepatic origin) (any level permitted), and/or unless felt to be clearlyrelated to disease where ≤ 5x institutional upper limit of normal is permitted,after discussion with the overall PI.

• AST(SGOT)/ALT(SGPT) ≤ 3x institutional upper limit of normal unless felt to beclearly related to disease where ≤ 5x institutional upper limit of normal ispermitted, after discussion with the overall PI.

• Total bilirubin - ≤1.5x institutional upper limit of normal (≤ 3x upper limit ofnormal in patients with known or suspected Gilbert's syndrome).

The effects of ASCIMINIB on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation.

• Women of child-bearing potential must agree to use highly effective methods ofcontraception during dosing and for 30 days after study treatment. Should a womanbecome pregnant or suspect she is pregnant while she or her partner is participatingin this study, she should inform her treating physician immediately.

• Allowable methods of birth control:

• Total abstinence (when this is in line with the preferred and usual lifestyleof the subject). Periodic abstinence (e.g., calendar, ovulation, symptothermal,post ovulation methods) and withdrawal are not acceptable methods ofcontraception.

• Female sterilization (have had surgical bilateral oophorectomy with or withouthysterectomy), total hysterectomy, or tubal ligation at least six weeks beforetaking study treatment. In case of oophorectomy alone, only when thereproductive status of the woman has been confirmed by follow up hormone levelassessment.

• Male sterilization (at least 6 months prior to screening). The vasectomizedmale partner should be the sole partner for that subject.

• Use of oral, injected or implanted hormonal methods of contraception orplacement of an intrauterine device (IUD) or intrauterine system (IUS), orother forms of hormonal contraception that have comparable efficacy (failurerate <1%), for example hormone vaginal ring or transdermal hormonecontraception.

• Sexually active males must use a condom during intercourse while taking the drug andfor 30 days after stopping treatment and should not father a child in this period. Acondom is required to be used also by vasectomized men in order to prevent deliveryof the drug via seminal fluid. -- Ability to understand and the willingness to signa written informed consent document and comply with all study procedures.

Exclusion Criteria:

• For dose escalation only: Participants suitable for and willing to receive standardintensive induction chemotherapy.

• Patients with a known ABL T315I mutation are excluded. ABL kinase mutation analysisis not recommended for newly diagnosed patient. ABL kinase mutation analysis isrecommended for patients with relapsed disease or CML progressed to blast phase onprior TKI, and results should be reviewed prior to enrollment.

• Prior treatment of ALL or CML with dasatinib or ASCIMINIB. Prior receipt of otherTKIs and chemotherapy for the treatment of ALL or CML is permitted.

• Any TKI therapy must be discontinued for 5 half-lives prior to initiation ofprotocol therapy.

• Patient may not have received other chemotherapy, including antibody-based therapy,within 2 weeks of the initiation of protocol therapy with the exception of steroids,hydroxyurea, ATRA, and/or intrathecal chemotherapy.

• Participants who are receiving any other investigational agents for conditions otherthan ALL must have discontinued those agents 2 weeks prior to the start of studytreatment.

• Impairment of gastrointestinal (GI) function or GI disease that may significantlyalter the absorption of study drug (e.g., ulcerative disease, uncontrolled nausea,vomiting, diarrhea, malabsorption syndrome). Patients who have had a gastrectomy arenot excluded.

• History of prior or concurrent malignancy requiring current treatment and/or whosenatural history has the potential to interfere with the safety or efficacyassessment of the investigational regimen. Indolent or low risk cancers (i.e. earlystage prostate cancer, early stage breast cancer, asymptomatic meningioma) judged tonot require treatment and/or have low potential for progression/recurrence afterappropriate therapy may be permitted after discussion with overall PI.

• Acute or chronic liver disease (including known active hepatitis B and Cinfections).

Screening for hepatitis is not required. Patients with known treated or past exposure viral hepatitis may participate after confirmation of absence of active infection (i.e. negative viral load).

• History of pulmonary arterial hypertension.

• Significant pleural effusions leading to respiratory compromise and need forintervention (i.e. thoracentesis).

• Alcohol abuse requiring medical treatment.

• Participants with a history of or current acute pancreatitis, chronic pancreatitis,or any ongoing pancreatic disease.

• Known human immunodeficiency virus (HIV). Screening is not required.

• History of a serious bleeding disorder unrelated to ALL.

• It is suggested that participants receiving treatment with medications that meet oneof the following criteria discontinue the relevant drug prior to the start oftreatment with ASCIMINIB and for the duration of the study. If the medication ismedically necessary, review with PI before enrollment.

• Strong inducers of CYP3A4/5.

• Moderate and strong inhibitors CYP3A4/5.

• CYP3A4/5, CYP2C8 and CYP2C9 substrates with narrow therapeutic index. All othersubstrates of the enzymes should be used with caution.

• H2 antagonists/proton-pump inhibitors.

• Grapefruit products are not permitted while on study.

• Because the lists of these agents are constantly changing, it is important toregularly consult a frequently-updated list such ashttp://medicine.iupui.edu/clinpharm/ddis/table.aspx; medical reference textssuch as the Physicians' Desk Reference may also provide this information.

As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product.

• Corrected QT interval (QTc) of > 480 milliseconds (ms) on baseline electrocardiogram (ECG) (using corrected QT interval per institutional standard).

• Major surgery within 2 weeks before the first dose of ASCIMINIB.

• Uncontrolled intercurrent illness including, but not limited to:

• Uncontrolled infection.

• Unstable cardiovascular condition including symptomatic congestive heartfailure (NYHA class 3 or 4), unstable angina pectoris, ongoing clinicallysignificant cardiac arrhythmia uncontrolled by medication, and myocardialinfarction or stroke within the past 3 months.

• Psychiatric illness/social situations that would limit compliance with studyrequirements.

• Currently requiring supplemental oxygen, mechanical ventilation, vasopressors,and/or hemodialysis (life-support).

• History of significant congenital or acquired bleeding disorder unrelated tocancer.

• Unable to comply with an oral regimen.

• Are pregnant or nursing at the time of screening. Pregnant women are excluded fromthis study because ASCIMINIB is an agent with the potential for teratogenic orabortifacient effects. Because there is an unknown but potential risk for adverseevents in nursing infants secondary to treatment of the mother with ASCIMINIB,breastfeeding should be discontinued if the mother is treated with ASCIMINIB. Thesepotential risks may also apply to other agents used in this study. Urine or serumpregnancy test must be performed within 14 days of Day 1 for women of childbearingpotential.