This research study is a Phase I clinical trial, which tests the safety of an investigational
drug and also tries to define the appropriate dose of the investigational drug to use for
further studies. "Investigational" means that the drug is being studied.
There is currently no clinical data on the effects of ABL001 in combination with dasatinib
and prednisone among adults with Ph+ B-ALL or CML in lymphoid blast crisis. However, there is
data on the use of ABL001 in combination with dasatinib (without steroids) in patients with
relapsed Ph+ B-ALL and Ph+ chronic myeloid leukemia (CML).
Dasatinib (Sprycel®) is currently approved for the treatment in newly diagnosed adults with
Ph+ CML in chronic phase (CP), adults with chronic, accelerated, or myeloid or lymphoid blast
phase Ph+ CML with resistance or intolerance to prior therapy including imatinib, adults with
Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) with resistance or
intolerance to prior therapy.
ABL001 is a newly discovered compound. This drug has been used in laboratory experiments and
information from those experiments suggest that this drug may have beneficial effects in
people who have CML or Ph+ ALL, both of which are a certain type of cancer of the blood
cells. The reason for this study is to learn whether ABL001 is safe and can have possible
benefits for people with Ph+ ALL who are also being treated with dasatinib and prednisone,
two drugs which are commonly used to treat Ph+ ALL. All participants in this study will
receive all three drugs.
Prednisone and dasatinib are both FDA approved and standard of care for participants with
your disease. They are not considered investigational on this study. However, ABL001 is being
tested in combination with these drugs.
Biomarker testing will also be included in this study. Biomarkers are important biological
"indicators" of whether a drug is working which can be measured from bone marrow and blood
samples.
In addition, blood and bone marrow samples may be tested to try to learn more about the
cancer, and to understand how the drug may be working in cancer.
Inclusion Criteria:
- Participants must meet the following criteria on screening examination to be eligible
to participate in the study:
- Participants must have cytopathologically confirmed BCR-ABL+ B-cell ALL or CML in
lymphoid blast crisis.20
- Patients with p210 (b2a2 or b3a2) and p190 (e1a2 only) transcripts confirmed by a
CLIA-certified lab assay will both be eligible.
- Patients with asymptomatic central nervous system (CNS) disease are eligible and
may be treated concurrently with intrathecal chemotherapy.
- Participants must NOT be suitable for or willing to receive standard 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
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.
- AST(SGOT)/ALT(SGPT) ≤ 3x institutional upper limit of normal.
- Total bilirubin ≤ 1.5x institutional upper limit of normal (≤ 3x upper limit of
normal in patients with known Gilbert's syndrome).
- The effects of ABL001 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) orintrauterine 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
- 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 and results should be reviewed prior to
enrollment.
- Prior treatment of ALL or CML with dasatinib or ABL001. 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
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 or
hydroxyurea for the control of leukocytosis.
- 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
treatment.
- 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 another active malignancy within 5 years prior to study entry except for
previous or concomitant basal cell skin cancer and previous carcinoma in situ treated
curatively.
- Acute or chronic liver disease (including known active hepatitis B and C infections).
Screening for hepatitis is not required. Patients with treated or past exposure viral
hepatitis (i.e. evidence of exposure negative viral load) may participate.
- 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 acute pancreatitis, chronic pancreatitis, or any
ongoing pancreatic disease not considered related to ALL.
- History of 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 at least one week prior to the
start of treatment with ABL001 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 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 ABL001.
- 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
requirements.
- Currently requiring supplemental oxygen, mechanical ventilation, vasopressors,
and/or hemodialysis (life-support).
- History of significant congenital or acquired bleeding disorder unrelated to
cancer.
- Unable to comply with an oral regimen.
- Are pregnant or nursing at the time of screening. Pregnant women are excluded from
this study because ABL001 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 ABL001,
breastfeeding should be discontinued if the mother is treated with ABL001. 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
potential
