Everolimus in Combination With Nelarabine, Cyclophosphamide and Etoposide in Lymphoblastic Leukemia/Lymphoma

NCT03328104 | Completed Phase 1 DMC FDA Drug

• 1 other identifier: IRB00095500
• Study Type: interventional
• Target: 8
• Locations: 1 country
• Sites: 4

Brief Summary

T- cell acute lymphoblastic leukemia (T-ALL) or T-cell lymphoblastic lymphoma (T-LLy) has an increase in proteins in a specific pathway called the mTOR pathway within the cancer cells. In cancer cells it can encourage untimely cell growth, cell production, and cell survival. Everolimus is an inhibitor of the mTOR pathway and can decrease the growth and survival of cancer cells. It also prevents communication within cells and stops proteins from being made that may contribute to leukemia. The main purpose of the study is to find the maximum tolerated dose of everolimus when used together with standard chemotherapy.

Conditions

Lymphoblastic Leukemia; Lymphoblastic Lymphoma

Keywords

T- cell acute lymphoblastic leukemia; T-ALL; T-cell lymphoblastic lymphoma; T-LLy; Everolimus; Maximum tolerated dose

Outcome Measures

Primary Outcomes (1)

• Determine the maximum tolerated dose (MTD).

  Maximum Tolerated Dose (MTD) will be defined as the highest dose level tested at which 0/6 or 1/6 patients experience Dose Limiting Toxicity (DLT) with at least 2/3 or 2/6 patients encountering DLT at the next higher dose.

  Day 1-29

Secondary Outcomes (7)

• Determine area under the concentration versus time curve (AUC)

  Day 1, 8 and 15 of course 1

• Determine maximum observed concentration (Cmax)

  Day 1, 8 and 15 of course 1

• Determine elimination half-life (t1/2)

  Day 1, 8 and 15 of course 1

• Changes in phosphoprotein (pAkt and p4EBP1) expression at time points pre- and post everolimus therapy in peripheral blood mono-nuclear cells (PBMCs) and bone marrow.

  Day 1, 8 and 15 and day 29/ at count recovery at the end of course 1 (whichever is earlier)

• Changes in Mer expression at time points pre- and post everolimus therapy in peripheral blood mono-nuclear cells (PBMCs) and bone marrow.

  Day 1, 8 and 15 and day 29/ at count recovery at the end of course 1 (whichever is earlier)

Study Arms (1)

Everolimus in combination with standard chemotherapy

EXPERIMENTAL

A treatment course lasts 28 days, during which participants take everolimus by mouth every day and also get standard chemotherapy via IV on certain days.

Drug: Everolimus; Drug: Nelarabine; Drug: Cyclophosphamide; Drug: Etoposide

Interventions

Everolimus DRUG

Given once daily orally via mouth or NG tube beginning at Dose Level (DL) 1 (4 mg/m2/day). Depending on safety and tolerability, dose levels will be escalated to DL2 (5 mg/m2/day). There is also a dose level de-escalation to DL0 (3 mg/m2/day) if toxicity is noted at DL1. Begins at Day 1 through 28.

Everolimus in combination with standard chemotherapy

Nelarabine DRUG

650 mg/m2 IV daily x Day 1-5

Everolimus in combination with standard chemotherapy

Cyclophosphamide DRUG

440 mg/m2 IV x Day 1-5

Everolimus in combination with standard chemotherapy

Etoposide DRUG

100 mg/m2 IV x Day 1-5

Everolimus in combination with standard chemotherapy

Eligibility Criteria

• Age: 2 Years - 29 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Age: Subjects must be \> than 1 year and \< 30 years of age at the time of study enrollment.
• Diagnosis Leukemia
• Patients must have relapsed (first or greater relapse) or refractory T-cell acute lymphoblastic leukemia (T-ALL) with:
• Relapsed T-ALL with an M2 (blasts ≥ 5 to ≤ 25%) or M3 (\>25% blasts) marrow with or without an extramedullary site of relapse; including CNS 2 OR
• Refractory disease after induction failure of newly diagnosed patients OR no more than two more cycles of therapy OR
• Refractory disease with no more than one prior salvage attempt following the current relapse
• Lymphoma
• Patients must have relapsed (first or greater relapse) or refractory lymphoma with:
• Lymphoblastic lymphoma or peripheral T-cell lymphoma.
• Histologic verification of disease at original diagnosis or subsequent relapse.
• Evaluable or measurable disease documented by clinical or radiographic criteria or bone marrow disease present at study entry.
• Patient may have CNS 2 status if other sites of leukemia or lymphoma involvement are present.
• Performance Score Patients must have a Karnofsky ≥ 50% for subjects \> 16 years of age and Lansky score ≥ 50 for subjects ≤ 16 years of age (See Appendix I).
• Note: Subjects who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.
• Prior Therapy A. Patients who relapse while receiving standard ALL maintenance chemotherapy will not be required to have a waiting period before entry onto this study.

You may not qualify if:

• Diagnosis
• Patients with CNS3 disease as defined in section 4.3.1
• Patients with isolated extra-medullary relapse involving only sanctuary sites (eg. Testicular relapse) but patients with extramedullary disease involving nodal or other non-sanctuary sites are eligible
• Patients with isolated testicular relapse
• Patients with Ph+ T-ALL/T-LLy
• Patients with Down Syndrome
• Patients with pre-existing Grade 2 (or higher) peripheral motor or sensory neurotoxicity per CTCAE 4.03
• Patients with a history of prior veno-occlusive disease (VOD)/sinusoidal obstruction syndrome (SOS) or findings consistent with a diagnosis of VOD/SOS, defined as: conjugated serum bilirubin \>1.4 mg/dL AND unexplained weight gain greater than 10% of baseline weight or ascites AND hepatomegaly or right upper quadrant pain without another explanation, OR reversal of portal vein flow on ultrasound, OR pathological confirmation of VOD on liver biopsy.
• Infection Criteria
• Positive blood culture within 48 hours of study enrollment;
• Fever above 38.2 within 48 hours of study enrollment with clinical signs of infection. Fever that is determined to be due to tumor burden is allowed if patients have documented negative blood cultures for at least 48 hours prior to enrollment and no concurrent signs or symptoms of active infection or hemodynamic instability.
• Active fungal, viral, bacterial, or protozoal infection requiring IV treatment. Chronic prophylaxis therapy to prevent infections is allowed
• Skin condition Patients with pre-existing Grade 1 or higher ulcerations, fistulas, mucosal lesions, or skin barrier breakdown
• Concomitant Medications
• Corticosteroids: Patients receiving corticosteroids who have not been on a stable or decreasing dose of corticosteroid for at least 7 days prior to enrollment are not eligible. Corticosteroids must be held for 24 hours prior to initiation of study therapy.

Sponsors & Collaborators

• Emory University: lead

Study Sites (4)

Children's Healthcare of Atlanta

Atlanta, Georgia, 30322, United States

Location

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

Location

Cincinnati Children's Hospital

Cincinnati, Ohio, 45229, United States

Location

Texas Children's Hospital

Houston, Texas, 77030, United States

Location

MeSH Terms

Conditions

Precursor Cell Lymphoblastic Leukemia-Lymphoma; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma

Interventions

Everolimus; nelarabine; Cyclophosphamide; Etoposide

Condition Hierarchy (Ancestors)

Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Sirolimus; Macrolides; Lactones; Organic Chemicals; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Phosphoramides; Organophosphorus Compounds; Podophyllotoxin; Tetrahydronaphthalenes; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Polycyclic Compounds; Glucosides; Glycosides; Carbohydrates

Study Officials

• Himalee Sabnis, MD

  Emory University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor

Study Record Dates

• First Submitted: October 20, 2017
• First Posted: November 1, 2017
• Study Start: July 24, 2018
• Primary Completion: June 29, 2023
• Study Completion: June 29, 2023
• Last Updated: July 21, 2023

Record last verified: 2023-07

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL
• Time Frame: Data will be available immediately following publication.
• Access Criteria: By contacting the principal investigator at hsabnis@emory.edu, following which a data use agreement will be needed for sharing data.

Locations

US (4)