A Phase 1 Study of ASCIMINIB in combination with dasatinib, prednisone, and blinatumomab in patients with BCR-ABL1 positive (BCR-ABL1+) B-cell acute lymphoblastic leukemia (B-ALL) and chronic myeloid leukemia (CML)

Protocol # :
B-cell Acute Lymphoblastic Leukemia
Chronic Myeloid Leukemia (CML) in Lymphoid Blast Crisis
Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia Ph+ ALL
Disease Sites
Lymphoid Leukemia
Myeloid and Monocytic Leukemia
Leukemia, other
Principal Investigator
Luskin, Marlise, R.
Site Investigator
Hock, Hanno, R.
Liegel, Jessica, J.
McMasters, Malgorzata
Mendez, Lourdes
Site Research Nurses
Aiken, Haley
Babcock, Elise
Bright, Susan
Green, Mallory
Knudsen, Elisabeth
Maciejewski, Ashley, Taylor
Smith, Caitlin
Toomey-Mathews, Ellen
Vartanian, Megan

Trial Description

This research study is evaluating a drug called ABL001 taken in combination with dasatinib
(Sprycel®) and prednisone (a steroid) as a possible treatment for B-cell Acute Lymphoblastic
Leukemia that is BCR-ABL positive (BCR-ABL+ B-ALL) or Chronic Myeloid Leukemia (CML) in
lymphoid blast crisis. BCR-ABL+ B-ALL is also called Philadelphia chromosome positive Acute
Lymphoblastic Leukemia (Ph+ ALL).

It is expected that 25-40 people will take part in this research study.

- ABL001

- Dasatinib (Sprycel®)

- Prednisone

- Blinatumomab

Eligibility Requirements

Inclusion Criteria:

- Participants must meet the following criteria on screening examination to be eligible
to participate in the study:

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

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

- Patients with asymptomatic central nervous system (CNS) disease are eligible
and may be treated concurrently with intrathecal chemotherapy.

- Dose escalation: Participants must NOT be suitable for or willing to receive
standard intensive induction chemotherapy.

- Dose expansion: Participants aged 18 years and older will be eligible regardless
of suitability for intensive induction chemotherapy.

The following groups are not considered suitable for standard intensive induction

- Participants who have not received standard intensive induction chemotherapy and are
aged ≥ 50 years.

- Participants who have not received standard intensive induction chemotherapy and are
aged 18 to 49 years and unfit due to co-morbidity or other factors to receive
intensive chemotherapy. Specific criteria that would suggest that a patient is
unsuitable for intensive induction chemotherapy include:

- Severe cardiac comorbidity (congestive heart failure or documented cardiomyopathy
with EF ≤50%).

- Severe pulmonary comorbidity (documented pulmonary disease with DLCO ≤ 65% or
FEV1 ≤ 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 with intensive
cytotoxic chemotherapy.

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

- ECOG performance status 0-3 (Appendix A). ECOG value of 3 is allowed after
documented discussion with PI, if poor performance status is attributed to
underlying 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 considered to
be not of hepatic origin) (any level permitted), and/or unless felt to be clearly
related 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 be clearly
related to disease where ≤ 5x institutional upper limit of normal is permitted, after
discussion with the overall PI.

- Total bilirubin - ≤1.5x institutional upper limit of normal (≤ 3x upper limit of
normal 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 of
contraception during dosing and for 30 days after study treatment. Should a woman
become pregnant or suspect she is pregnant while she or her partner is participating
in 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 lifestyle of
the subject). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post
ovulation methods) and withdrawal are not acceptable methods of contraception.

- Female sterilization (have had surgical bilateral oophorectomy with or without
hysterectomy), total hysterectomy, or tubal ligation at least six weeks before
taking study treatment. In case of oophorectomy alone, only when the reproductive
status of the woman has been confirmed by follow up hormone level assessment.

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

- Use of oral, injected or implanted hormonal methods of contraception or placement
of an intrauterine device (IUD) or intrauterine system (IUS), or other forms of
hormonal contraception that have comparable efficacy (failure rate <1%), for
example hormone vaginal ring or transdermal hormone contraception.

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

Exclusion Criteria:

- For dose escalation only: Participants suitable for and willing to receive standard
intensive induction chemotherapy.

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

- Prior treatment of ALL or CML with dasatinib or ASCIMINIB. Prior receipt of other TKIs
and chemotherapy for the treatment of ALL or CML is permitted.

- Any TKI therapy must be discontinued for 5 half-lives prior to initiation of protocol

- 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 other
than ALL must have discontinued those agents 2 weeks prior to the start of study

- Impairment of gastrointestinal (GI) function or GI disease that may significantly
alter the absorption of study drug (e.g., ulcerative disease, uncontrolled nausea,
vomiting, diarrhea, malabsorption syndrome). Patients who have had a gastrectomy are
not excluded.

- History of prior or concurrent malignancy requiring current treatment and/or whose
natural history has the potential to interfere with the safety or efficacy assessment
of the investigational regimen. Indolent or low risk cancers (i.e. early stage
prostate cancer, early stage breast cancer, asymptomatic meningioma) judged to not
require treatment and/or have low potential for progression/recurrence after
appropriate therapy may be permitted after discussion with overall PI.

- Acute or chronic liver disease (including known active hepatitis B and C infections).

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 for
intervention (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 one
of the following criteria discontinue the relevant drug prior to the start of
treatment with ASCIMINIB and for the duration of the study. If the medication is
medically 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 other
substrates 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 to
regularly consult a frequently-updated list such as
http://medicine.iupui.edu/clinpharm/ddis/table.aspx; medical reference texts such
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

- 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 heart failure
(NYHA class 3 or 4), unstable angina pectoris, ongoing clinically significant
cardiac arrhythmia uncontrolled by medication, and myocardial infarction or
stroke within the past 3 months.

- Psychiatric illness/social situations that would limit compliance with study

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

- History of significant congenital or acquired bleeding disorder unrelated to

- Unable to comply with an oral regimen.

- Are pregnant or nursing at the time of screening. Pregnant women are excluded from
this study because ASCIMINIB is an agent with the potential for teratogenic or
abortifacient effects. Because there is an unknown but potential risk for adverse
events in nursing infants secondary to treatment of the mother with ASCIMINIB,
breastfeeding should be discontinued if the mother is treated with ASCIMINIB. These
potential risks may also apply to other agents used in this study. Urine or serum
pregnancy test must be performed within 14 days of Day 1 for women of childbearing