Carfilzomib in Combination With Cyclophosphamide and Etoposide for Children (POE14-01)

Phase I Study of Carfilzomib in Combination With Cyclophosphamide and Etoposide for Children With Relapsed and Refractory Solid Tumors and Leukemias

This study evaluates the use of carfilzomib in combination with cyclophosphamide and etoposide for children with relapsed/refractory solid tumors or leukemia. The medications cyclophosphamide and etoposide are standard drugs often used together for the treatment of cancer in children with solid tumors or leukemia.

Carfilzomib is FDA (Food and Drug Administration) approved in the United States for adults with multiple myeloma (a type of cancer). However, this drug is not approved to treat children with relapsed/refractory solid tumors or leukemia. With this research, we plan to determine the DLTs and MTD of Carfilzomib given in combination with cyclophosphamide and etoposide in pediatric patients with relapsed/refractory leukemias and solid tumors.

Study Overview

• Status: Completed
• Conditions: Refractory Leukemia; Refractory Solid Tumors; Relapsed Solid Tumors; Relapsed Leukemia
• Intervention / Treatment: Drug: Cyclophosphamide; Drug: Etoposide; Drug: Carfilzomib

Detailed Description

Part 1 of the study will include a dose escalation based on Dose limiting toxicities (DLTs) until the MTD or highest dose level is reached, whichever comes first.

At the MTD or highest dose level (if no MTD is reached), an additional 6 patients will be enrolled to further evaluate safety of the regimen (Part 2).

Part 2 of this study will enroll additional patients at the highest tolerable dose found in Part 1 in order to get more information on side effects and make sure the dose is tolerable

Once an MTD is determined for Strata A or B, if the Study Principal Investigator determines that the study treatment should not be further pursued due to safety or enrollment barriers, the expansion Part or the study will be discontinued.

• Study Type: Interventional
• Enrollment (Actual): 4
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Norman Lacayo, MD; Phone Number: 650-723-5533; Email: lacayon@stanford.edu
• Study Contact Backup: Name: Aru Narendran, MD, PhD; Phone Number: 403-210-6418; Email: anarendr@ucalgary.ca

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada, T3B 6A8
      • Alberta Children's Hospital
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85016
      • Phoenix Children's Hospital
  • Arkansas
    • Little Rock, Arkansas, United States, 72202
      • Arkansas Children's Hospital
  • California
    • Palo Alto, California, United States, 94304
      • Stanford University School of Medicine and Stanford Cancer Institute
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana Farber Cancer Institute
  • New York
    • New York, New York, United States, 10065
      • Memorial Sloan-Kettering Cancer Center
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033-0850
      • Penn State Hershey Children's Hospital
  • Texas
    • San Antonio, Texas, United States, 78229
      • University of Texas Health Science Center at San Antonio

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 months to 29 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Patients must have either of the following:

   1. Relapsed/refractory leukemia in 2nd or greater relapse or who have failed at least one re-induction attempt after relapse or for refractory disease. Patients must meet the WHO classification with ≥ 5% blasts in the bone marrow or must have definitive extramedullary disease (e.g. chloromas, skin lesions). Patients may have asymptomatic CNS 1 or CNS 2 disease, but not CNS 3 or symptomatic CNS disease.

      OR

   2. Relapsed/refractory non-CNS solid tumor that has not responded or has relapsed and for which no standard treatment is available. Patients may not have primary CNS tumors or CNS metastases. Lymphoma patients are permitted. Patients do not need to have measurable disease.
2. Age 6 months - 29.99 years at enrollment
3. Life expectancy ≥ 3 months
4. Lansky or Karnofsky ≥50

5. Prior therapy

   1. Patient must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, radiotherapy, or surgery prior to study entry.
   2. Myelosuppressive therapy- At least 14 days must have elapsed since the administration of previous therapy. Six weeks must have elapsed from the administration of nitrosureas or mitomycin C. For patients with ALL on maintenance therapy, they may be eligible if 7 days have elapsed and they are recovered from the toxic effects of the chemotherapy. This restriction does not include intrathecal chemotherapy, which is permitted.
   3. Biologic agents- At least 14 days must have elapsed since the completion of therapy with a biologic agent such as a monoclonal antibody. Seven days must have elapsed since the last dose of retinoids
   4. Radiation therapy - At least 14 days must have elapsed for local XRT. At least 90 days must have elapsed if prior radiation to ≥50% of the pelvis, the spine, or other substantial bone marrow radiation including TBI.
   5. Hematopoietic growth factors- At least 7 days must have elapsed since the last dose of G-CSF or GM-CSF. At least 14 days must have elapsed since last dose of pegfilgrastim (Neulasta®).
6. Patient must be ≥ 3 months from hematopoietic stem cell transplant, must not have active GVHD, and must be off all immunosuppression

7. Organ function:

   1. Either a serum creatinine ≤ ULN for age, or calculated or measured GFR ≥ 70 mL/min/1.73 m2
   2. Total bilirubin ≤ 1.5 x ULN for age, direct bilirubin ≤ ULN for age
   3. AST and ALT ≤ 3 x ULN for age unless elevation can be clearly attributed to liver leukemia or metastases
   4. ECHO shortening fraction ≥ 27%
   5. Pulse Oximetry measurement ≥ 95% saturation without supplemental oxygen

8. Bone marrow function:

   1. Hgb ≥10 g/dL - can be transfused
   2. Plts ≥ 75,000 - cannot be transfused (must be ≥ 7 days from last plt transfusion)
   3. ANC ≥ 750 - cannot be transfused (must be ≥ 72 hours from last neutrophil infusion)

   However, the plt and ANC requirements can be waived if low counts thought to be secondary to leukemia or tumor bone marrow infiltration

9. Reproductive function:

   1. Female patients of childbearing potential must have a negative serum pregnancy test confirmed within 7 days prior to enrollment
   2. Female patients with infants must agree not to breastfeed their infants while on the study
   3. Male and female patients of child-bearing potential must agree to use an effective method of contraception approved by the investigator during the study and for a minimum of 3 months after study treatment
10. Written informed consent

Exclusion Criteria:

1. Prior treatment with carfilzomib
2. Known allergy to Captisol® (a cyclodextrin derivative used to solubilize carfilzomib).
3. Down syndrome
4. Fanconi Anemia or other underlying bone marrow failure syndrome
5. Pregnant or lactating females
6. Known history of Hepatitis B or C or HIV
7. Patient with any significant concurrent illness
8. Patient with uncontrolled systemic fungal, bacterial, viral or other infection with ongoing signs/symptoms despite appropriate treatment
9. Patient with illness, psychiatric disorder or social issue that could compromise patient safety or compliance with the protocol treatment or procedures, or interfere with the consent, study participation, follow-up, or interpretation of study results.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Carfilzomib; Carfilzomib in combination with cyclophosphamide and etoposide	Drug: Cyclophosphamide; Drug: Etoposide; Drug: Carfilzomib; Carfilzomib in combination with cyclophosphamide and etoposide for children with relapsed and refractory solid tumors and leukemias

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
To determine the DLTs and MTD of carfilzomib given in combination with cyclophosphamide and etoposide in pediatric patients with relapsed/refractory leukemias and solid tumors	30 Days post treatment initiation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To evaluate toxicities of carfilzomib in the pediatric population when combined with conventional chemotherapy.	Record AEs and SAEs	Treatment initiation through 30 days post treatment
Determine patient response rate (CR, PR, SD, PD) with this regimen		Treatment initiation through 30 days post treatment
To measure if circulating plasma proteosome (cProt) levels post treatment correlate with response to therapy and overall survival.		Treatment initiation through 30 days post treatment
To measure if the levels of proteasome activity and resistance to carfilzomib correlates with toxicity and/or response to treatment		Treatment initiation through 30 days post treatment
To measure if inhibition of proteasome activity by carfilzomib results in alteration in a number of autophagy and apoptosis related proteins, providing means to evaluate correlates of activity of carfilzomib		Treatment initiation through 30 days post treatment
To measure the level of proteosome inhibition in patient PBMCs before and during treatment by determination of the level of protein ubiquitination		Treatment initiation through 30 days post treatment
To determine in vitro sensitivity of patient leukemias and solid tumors to carfilzomib alone and in combination with study chemotherapeutic agents in order to generate a predictive model of drug sensitivity		Treatment initiation through 30 days post treatment
To perform whole exome sequencing (WES) and RNA seq on patient leukemia and solid tumor samples and WES on germ line DNA in order to determine potential mechanisms of drug sensitivity or resistance		Treatment initiation through 30 days post treatment

Collaborators and Investigators

• Sponsor: Stanford University
• Collaborators: Amgen; Pediatric Oncology Experimental Therapeutics Investigators' Consortium

Study record dates

Study Major Dates

• Study Start (Actual): February 16, 2016
• Primary Completion (Actual): August 28, 2021
• Study Completion (Actual): November 7, 2023

Study Registration Dates

• First Submitted: July 21, 2015
• First Submitted That Met QC Criteria: July 28, 2015
• First Posted (Estimated): July 31, 2015

Study Record Updates

• Last Update Posted (Actual): January 12, 2024
• Last Update Submitted That Met QC Criteria: January 10, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Relapsed; Refractory; Leukemia; Solid Tumors
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Leukemia; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Cyclophosphamide; Etoposide
• Other Study ID Numbers: IRB-37313; PEDSVAR0042 (Other Identifier: Stanford - OnCore)