This research study is studying a combination of two targeted therapies as a possible
treatment for acute myeloid leukemia (AML) that has relapsed after initial treatment or did
not fully respond.
The name of the study interventions involved in this study are:
- Merestinib
- LY2874455
- This research study is a Phase I clinical trial, which tests the safety of an
investigational intervention and also tries to define the appropriate dose of the
investigational intervention to use for further studies. "Investigational" means that
the intervention is being studied.
- The FDA (the U.S. Food and Drug Administration) has not approved Merestinib or LY2874455
as a treatment for any disease.
- Merestinib is an oral drug known as a MET kinase inhibitor that is being developed as a
treatment for patients with advanced cancer. MET inhibitors work by stopping a signal
that a cell receives instructing it to grow.
- LY2874455 is an oral drug known as an FGFR inhibitor that is also being developed as a
treatment for patients with advanced cancer. FGFR inhibitors work by stopping a signal
that a cell receives instructing it to grow.
- In this research study, the investigators are investigating whether Merestinib and
LY2874455 is safe to give in combination in patients with AML. In previous laboratory
studies, it was found that leukemia cells responded to treatment with a MET inhibitor
and an FGFR inhibitor. However, it is not yet known whether this will also be the case
with LY2874455 and merestinib when given to participants.
Inclusion Criteria:
- Participants must have pathologically confirmed relapsed or refractory acute myeloid
leukemia (AML) or secondary AML following IWG criteria [40].
- For subjects with relapsed AML: evidence of ≥ 5% blasts in the bone marrow or
development of extramedullary disease who relapse after:
- Allogeneic hematopoietic stem cell transplant, or
- A minimum of one cycle of standard cytotoxic chemotherapy or two cycles of
any hypomethylating agent-based therapy
- For subjects with refractory AML: a minimum of 2 prior induction regimens
(example: patients who receive 7+3 followed by 5+2 would count as one induction
regimen) or a minimum of two cycles of any hypomethylating agent-based therapy.
- For subjects with secondary AML: untreated secondary AML, must have been
previously treated for myelodysplastic syndrome (MDS) or myeloproliferative
neoplasms (MPN) or MDS/MPN (MDS/MPN) overlap syndrome.
- No limit to number of prior therapies.
- Patients are considered to have failed available therapies or to be ineligible for or
to not be interested in intensive chemotherapies, including allogeneic hematopoietic
stem cell transplantation.
- Patients with a history of allogeneic stem cell transplantation are eligible for study
participation provided the transplant was > 100 days prior to study enrollment.
Patients must not have active graft versus host disease other than grade 1 skin
involvement.
- Age 18 and older.
- ECOG performance status ≤2 (see Appendix A).
- Participants must have normal organ and marrow function as defined below:
- Direct bilirubin within ≤ 1.5 times the institutional upper limit of normal
(ULN). For patients with known Gilbert Syndrome, or if the elevation is believed
to be leukemia related, the cut-off of ≤ 3.0 times the institutional ULN is
allowable.
- AST(SGOT)/ALT(SGPT) ≤2.5 × institutional ULN, unless believed to be leukemia
related then ≤ 5 x ULN is allowed.
- Serum creatinine ≤ 2.0 x ULN
- Females of child bearing potential and males must agree to use barrier method/hormonal
methods from start of study until four months after last dose of study drug. Females
of child bearing potential must have a negative serum pregnancy test at screening.
Females are not considered to be of child bearing potential if they are status post
successful surgical sterilization including hysterectomy, bilateral tubal ligation or
bilateral oophorectomy, or if they are postmenopausal (absence of menses for 12
consecutive months that is not secondary to prior chemotherapy, anti-estrogens,
ovarian suppression or other reversible cause).
- The effects of Merestinib and LY2874455 on the developing human fetus are unknown.
Small molecular inhibitors of tyrosine kinase receptors are known to be teratogenic.
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.
- Ability to understand and the willingness to sign a written informed consent document.
- Able and willing to undergo the required bone marrow biopsies. Correlative studies are
strongly encouraged.
Exclusion Criteria:
- Participants who have had radiotherapy within 2 weeks, with the exception of localized
radiotherapy to palliate extramedullary leukemia where no washout is required.
- Participants who have had chemotherapy within 2 weeks or 5 half-lives (whichever is
longer) from the last dose of chemotherapy prior to entering the study or those who
have not recovered from adverse events due to agents administered more than 2 weeks
earlier. Hydroxyurea is allowed per treating investigator. IT chemotherapy prophylaxis
is permitted.
- Participants who are receiving any other investigational agents, with the exception of
topical or ophthalmologic therapies for mild graft versus host disease which are
permitted.
- Participants with known CNS leukemia involvement should be excluded from this clinical
trial because of their poor prognosis and because they often develop progressive
neurologic dysfunction that would confound the evaluation of neurologic and other
adverse events.
- Individuals with other active malignancies that require concurrent chemotherapy are
ineligible. Hormone therapy is allowed.
- Subject has a known gastrointestinal disorder that in the opinion of the treating
investigator is concerning for malabsorption of oral medications.
- Subject is unable to swallow pills.
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements. Patients with current or history of NYHA class III or IV cardiac
disease, myocardial infarction with past 6 months, or unstable arrhythmia will be
ineligible for study.
- Pregnant women are excluded from this study because Merestinib and LY2874455 have 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 Merestinib and LY2874455, breastfeeding should be discontinued if the
mother is treated with Merestinib and LY2874455.
- HIV-positive participants on combination antiretroviral therapy are ineligible because
of the potential for pharmacokinetic interactions with Merestinib and LY2874455. In
addition, these participants are at increased risk of lethal infections when treated
with marrow-suppressive therapy. Appropriate studies will be undertaken in
participants receiving combination antiretroviral therapy when indicated.
- Subjects with QTcF interval of ≥ 450 msec if male and ≥ 470 msec if female following
or with other factors increase the risk of QT prolongation or arrhythmic events (e.g.
heart failure, hypokalemia, family history of long QT interval syndrome) at screening.
Subjects with bundle branch block should be reviewed by the Medical Monitor for
potential inclusion.
- Subjects with known active HBV or HCV (cannot have an elevated viral load of HBV or
HCV if known history) are ineligible
