Ribociclib in Combination With Everolimus and Dexamethasone in Relapsed ALL

Status: Recruiting
Phase:
DFCI Protocol ID: 18-328

This research study is evaluating a drug called ribociclib (LEE011) given in combination with everolimus and other standard of care chemotherapy drugs as a possible treatment for relapsed or refractory ALL. The names of the drugs involved in this study are: - ribociclib - everolimus - dexamethasone

Conducting Institutions:

Children's Hospital Boston, Dana-Farber Cancer Institute

Overall PI:

Site-responsible Investigators:

Contacts:

Eligibility Criteria

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

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