Ribociclib in Combination With Everolimus and Dexamethasone in Relapsed ALL

This research study is a Phase I clinical trial, which tests the safety of an investigational
drug or a combination of drugs. Phase I studies try to define the appropriate dose of the
investigational drug to use for further studies. "Investigational" means that the drug and
the combination of drugs are still being studied.

The FDA (the U.S. Food and Drug Administration) has not approved the study drugs, ribociclib
or everolimus, for relapsed ALL, but these drugs have been approved for other uses.

Ribociclib is a chemotherapy drug that is approved by the FDA for the treatment of certain
types of breast cancer. It has also been studied in children and adults with other types of
cancer. Information from these research studies has suggested that ribociclib may also be
effective in treating participants with leukemia that did not respond to standard treatment
or participants with leukemia that has come back after standard treatment.

The growth and survival of leukemia cells is controlled by proteins within the cancer cell.
The study drug, ribociclib, blocks a specific type of protein called a cyclin-dependent
kinases (CDK). Laboratory and other studies suggest that when ribociclib blocks CDKs, cancer
cells stop growing.

Everolimus is a chemotherapy drug that is approved by the FDA for the treatment of breast
cancer, neuroendocrine tumor and kidney cancer. Laboratory and other studies suggest that
everolimus may prevent leukemia cell growth and also that it has been shown to increase the
effectiveness of other chemotherapy drugs, including ribociclib. It has been studied in
hundreds of people with various types of cancer as a single agent (a drug that is used alone
to treat the cancer) or in combination with a number of other drugs.

The drug combination of ribociclib and everolimus has not been previously tested in children,
though these agents have been used together in adults with breast cancer.

In this research study the investigators are looking to learn more about how ribociclib and
everolimus work in combination with other standard of care drugs commonly used to treat
relapsed/refractory leukemia. The main goals of the study are:

- To evaluate the side effects (good and/or bad) of giving ribociclib in combination with
other standard of care drugs.

- To determine the highest dose of ribociclib and everolimus that can be given safely in
combination with other standard of care drugs.

- To determine the amount of ribociclib and everolimus in the blood when it is given in
combination with other standard of care drugs.

Inclusion Criteria:

- Age > 12 months (365 days) and ≤ 30 years

- Histologically confirmed diagnosis of relapsed or refractory ALL

- Primary refractory disease: Persistent disease after at least two induction
attempts

- Relapsed disease: Second or subsequent relapse, or any relapse refractory to
salvage chemotherapy

- Participants must have bone marrow with ≥ 1% lymphoblasts definitively identified
either on a bone marrow aspirate or biopsy sample, as assessed by morphology,
immunohistochemical studies, flow cytometry, karyotype, cytogenetic testing such as
fluorescent in situ hybridization (FISH) or other molecular studies.

- Participants with CNS1 or CNS2 disease are eligible. Patients with isolated CNS
relapse or CNS 3 disease are not eligible. (Refer to Section 12.4 for definitions of
CNS status)

- Participants must have fully recovered from the acute toxic effects of all prior
chemotherapy, immunotherapy, or radiotherapy prior to entering this study and meet all
of the following criteria:

- Corticosteroids: 14 days must have elapsed since the completion of systemic
corticosteroid administration. The following uses of corticosteroids are permitted:
single doses (e.g., during anesthesia), topical applications (e.g., for rash), inhaled
sprays (e.g., for obstructive airway diseases, asthma), eye drops or local injections
(e.g., intra-articular)

- Myelosuppressive chemotherapy: 14 days must have elapsed since the completion of
myelosuppressive therapy. Individuals may have received any of the following
medications within 14 days without a "wash-out" period:

- Standard maintenance therapy, other than corticosteroids (vincristine, 6MP, low
dose methotrexate)

- Hydroxyurea

- Intrathecal chemotherapy with methotrexate, hydrocortisone and/or cytarabine.

- Radiation therapy (XRT):

- Total Body Irradiation (TBI) or cranial radiation therapy: Must have been
completed more than 90 days prior to study entry

- XRT for chloroma does not require a washout period.

- Palliative XRT does not require a washout

- Small molecule inhibitors (BCR-ABL or FLT3 inhibitors, for example): 7 days must have
elapsed since the completion of therapy. For agents that have known adverse events
occurring beyond 7 days after administration, this period must be extended beyond the
time during which adverse events are known to occur. The duration of this interval
must be discussed with the Study Chair.

- Immunotherapy: At least 6 weeks after the administration of any type of immunotherapy,
including, but not limited to, tumor vaccines, chimeric antigen receptor (CAR)
therapy, other immune effector cell therapy or checkpoint inhibitors.

- Monoclonal antibodies: At least 3 half-lives of the antibody after the last dose of a
monoclonal antibody. (See table on DVL homepage listing monoclonal antibody
half-lives: https://members.childrensoncologygroup).

- Prior hematopoietic stem cell transplant (HSCT): Patients who have received HSCT are
eligible, but must meet all of the following conditions:

- Autologous HSCT > 60 days of study entry

- Allogeneic HSCT > 90 days of study entry

- No evidence of graft-versus-host-disease (GVHD)

- Weaning or stable doses of calcineurin inhibitors are permitted provided there is
no evidence of active GVHD.

- Participants must have a body surface area (BSA) ≥ 0.4 m2.

- Performance status:

--Lansky > 50 for individuals < 16 years old; Karnofsky > 50% for individuals ≥ 16
years old (See Appendix A).

- Participants must have adequate organ function as defined by the following laboratory
values:

- Direct bilirubin ≤1.5 X institutional upper limit of normal (ULN).

- Alanine aminotransferase (ALT) < 3 x ULN for age and aspartate aminotransferase
(AST) < 3 x ULN for age. Patients with leukemic infiltration of the liver must
have AST and ALT < 5 x ULN for age.

- Creatinine below institutional ULN or creatinine clearance > 60 mL/min/1.73 m2
for subjects with creatinine levels above institutional normal.

- Echocardiogram ejection fraction ≥50%. Echocardiogram must be obtained while patient
is not receiving cardiotropic medications (e.g., pressors or afterload reducers).

- QTc < 450 ms on screening ECG.

- Oxygen saturation ≥ 90% by pulse oximetry without administration of supplemental
oxygen.

- Female patients of childbearing potential must have a negative urine or serum
pregnancy test confirmed prior to enrollment.

- Female patients with infants must agree not to breastfeed their infants while on this
study.

- 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. Should a woman become pregnant or suspect she is
pregnant while participating in this study, she should inform her treating physician
immediately.

- Ability to understand and/or the willingness of the patient (or parent or legally
authorized representative, if minor) to provide informed consent, documented using an
institutionally approved informed consent procedure

Exclusion Criteria:

- Impairment of gastrointestinal (GI) function or GI disease that may significantly
alter the absorption of ribociclib, everolimus or dexamethasone (e.g., ulcerative
diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small
bowel resection).

- Individuals with CNS 3 leukemia at time of study entry. History of CNS 3 disease is
allowable as long as patient meets eligibility criteria (CNS 1 or 2) at time of
enrollment.

- Individuals with Down syndrome.

- Treatment with hematopoietic growth factors (G-CSF):

- Long-acting (e.g., Neulasta) within 14 days prior to study entry

- Short-acting (e.g., Neupogen) within 7 days prior to study entry

- Treatment with an investigational agent within 28 days of study entry, or 3
half-lives, whichever is longer.

- Patients will be excluded if there is a plan to administer non-protocol chemotherapy,
radiation therapy, or immunotherapy during the study period.

- Clinically significant, uncontrolled heart disease and/or cardiac repolarization
abnormalities, including any of the following:

- History of acute coronary syndromes (including myocardial infarction, unstable
angina, coronary artery bypass grafting, coronary angioplasty, or stenting) or
symptomatic pericarditis within 6 months prior to screening

- History of documented congestive heart failure (New York Heart Association
functional classification III-IV)

- Cardiomyopathy

- Clinically significant cardiac arrhythmias (e.g. ventricular tachycardia),
complete left bundle branch block, high-grade AV block (e.g. bifascicular block,
Mobitz type II and third-degree AV block)

- Long QT syndrome or family history of idiopathic sudden death or congenital long QT
syndrome, or any of the following:

- Risk factors for Torsades de Pointe (TdP) including uncorrected hypokalemia or
hypomagnesemia, history of cardiac failure or history of significant/symptomatic
bradycardia.

- Concomitant use of medication(s) with a known risk to prolong the QT interval
and/or known to cause Torsades de Pointe that cannot be discontinued (within 5
half-lives or 7 days prior to starting study drug) or replaced by safe
alternative medication (See Appendix C for list of prohibited medications)

- Inability to determine the QTcF interval on screening EKG (using Fridericia's
correction)

- Prior exposure to a CDK4/6 inhibitor

- Patient is currently receiving any of the following medications and cannot be
discontinued 7 days prior to starting study drug (see Appendix C for prohibited
medications):

- Known strong inducers or inhibitors of CYP3A4/5, including grapefruit, grapefruit
hybrids, pummelos, star-fruit, and Seville oranges

- Medications with a narrow therapeutic window that are predominantly metabolized
through CYP3A4/5

- Herbal preparations/medications, dietary supplements.

- Patients refractory to red blood cell or platelet transfusions.

- Patient is currently receiving warfarin or other coumarin-derived anticoagulant for
treatment, prophylaxis or otherwise. Therapy with heparin, low molecular weight
heparin (LMWH) or fondaparinux is allowed.

- Patients with systemic fungal, bacterial, viral or other infection that is exhibiting
ongoing signs/symptoms related to the infection without improvement despite
appropriate antibiotics or other treatment.

- Patients known to have human immunodeficiency virus (HIV) infection; baseline testing
for HIV is not required.

- Patients known to have active hepatitis A, B, or C infection; or known to be positive
for HCV RNA or HBsAg (HBV surface antigen); baseline testing for viral hepatitis is
not required.

- Major surgery within 2 weeks of the first dose of study drugs. The following are not
considered major surgery for the purposes of eligibility: Tumor biopsy, insertion of a
gastric feeding tube, central venous access.

- Individuals with significant concurrent disease, illness, psychiatric disorder or
social issue that would compromise patient safety or compliance, interfere with
consent, study participation, follow up, or interpretation of study results.

- Individuals with a history of a different malignancy (other than ALL) are ineligible
except for the following circumstances:

- Individuals are eligible if they have been disease-free for at least 5 years and
are deemed by the investigator to be at low risk for recurrence of that
malignancy.

- Individuals with the following cancers are eligible if diagnosed and treated
within the past 5 years: cervical cancer in situ, and basal cell or squamous cell
carcinoma of the skin.

- Pregnant or nursing women are excluded