Bridging Study to Eliminate Presence of MRD for Acute Leukemia Before HCT

• Sponsor: Medical College of Wisconsin (Other)
• Overall Status: Terminated
• CT.gov ID: NCT02349178
• Collaborator: American Family Children's Hospital (Other), Nationwide Children's Hospital (Other)
• Enrollment: 6
• Locations: 4
• Arm: 1
• Actual Duration (Months): 27.2
• Patients Per Site: 1.5
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This is a Phase 2 study designed for the purpose of estimating various parameters surrounding the efficacy of Clofarabine, Cyclophosphamide and Etoposide in eliminating minimal residual disease (MRD) in acute leukemia patients otherwise in remission and without causing significant delay of HCT due to treatment related toxicity.

A single course of "bridge" chemotherapy is given prior to the transplant procedure as an approach to improved disease-free survival in a patient group who historically has had inferior outcomes.

Condition or Disease	Intervention/Treatment	Phase
Leukemia, Acute Lymphoblastic; Acute Myeloid Leukemia	Drug: Clofarabine; Drug: Cyclophosphamide; Drug: Etoposide	Phase 2

Detailed Description

Study entry is open to patients regardless of gender or ethnic background.

The intent of this study design is for all patients to receive and complete one course of therapy. Patients who exhibit signs of disease progression or experience an unacceptable toxicity will be discontinued from treatment.

There will be no dose delays or dose reductions of study drugs for hematologic toxicity during Consolidation "Bridging" therapy (Day 1 through Day 30); however, prolonged hematopoietic recovery or bone marrow aplasia during the first 42 days may meet a study stopping rule.

Study Design

• Study Type: Interventional
• Actual Enrollment: 6 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Bridging Study: A Phase 2 Study Investigating Clofarabine, Cyclophosphamide and Etoposide for Children, Adolescents, and Young Adults (AYA) With Acute Leukemia and Minimal Residual Disease
• Actual Study Start Date: Dec 8, 2014
• Actual Primary Completion Date: Mar 16, 2017
• Actual Study Completion Date: Mar 16, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Bridging Arm Days 1-5 Receive 20 mg/m2 IV Clofarabine (CLOLAR) over 2 hours followed by 100 mg/m2 IV Etoposide (VP-16, Etopophos) over 2 hours followed by 300 mg/m2 IV Cyclophosphamide (Cytoxan, CTX) as a 30-60 minute infusion	Drug: Clofarabine; Days 1-5 receive Clofarabine 20 mg/m2 IV over 2 hours; Other Names: CLOLAR ; Drug: Cyclophosphamide; Days 1-5 receive Cyclophosphamide 300 mg/m2 IV as a 30-60 minute infusion; Other Names: Cytoxan, CTX ; Drug: Etoposide; Days 1-5 receive Etoposide 100 mg/m2 IV over 2 hours; Other Names: VP-16, Etopophos

Outcome Measures

Primary Outcome Measures

1. Minimal Residual Disease [Day 30 or adequate blood recovery]

   A bone marrow evaluation to determine study response and remission status will be performed on study Day 30 or upon adequate blood count recovery (ANC > 0.50 and platelet > 50,000), whichever occurs first. If the marrow is hypocellular and without evidence of normal tri-lineage hematopoiesis the marrow should be repeated at Day 42.

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A to 39 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Diagnosis of acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML) with < 5% blasts in the bone marrow (M1) by morphology and that meets one of the following criteria:

Flow cytometric evidence of MRD (≥ 0.01% leukemic blasts for ALL or ≥ 0.5% leukemic blasts for AML detected in the bone marrow) OR Molecular/cytogenetic evidence of disease (FISH or PCR methodology) performed within 7 days And with the intent of going on to an allogeneic hematopoietic cell transplantation (HCT) independent of this study

• Patients must have an available donor and have intention of proceeding directly to ALL-HCT after completion of 1 cycle of Bridging therapy.

• Age 0 to 39 years

• Karnofsky Performance Status ≥ 50% for patients 16 years and older and Lansky Play Score ≥ 50 for patients under 16 years of age (see Appendix 2)

• Patients must have a life expectancy ≥ 8 weeks as determined by the enrolling investigator

• Have acceptable organ function as defined within 7 days of study registration

Renal: creatinine clearance ≥ 60 mL/min/1.73 m2 or serum creatinine based on age/gender as follows:

Hepatic: ALT < 5 x upper limit of normal (ULN) and total bilirubin ≤ 1.5 x upper limit of normal (ULN) for age Cardiac: left ventricular ejection fraction ≥ 40% by ECHO/MUGA

• Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study. At least 7 days must have elapsed from prior chemotherapy.

• Hematopoietic Growth Factors: At least 7 days since the completion of therapy with a growth factor and at least 14 days since pegfilgrastim (Neulasta®) administration.

• Sexually active females of child bearing potential must agree to use adequate contraception (diaphragm, birth control pills, injections, intrauterine device [IUD], surgical sterilization, subcutaneous implants, or abstinence, etc.) for the duration of treatment and for 2 months after the last dose of chemotherapy. Sexually active men must agree to use barrier contraceptive for the duration of treatment and for 2 months after the last dose of chemotherapy.

• Voluntary written consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care.

Exclusion Criteria:

• Acute Promyelocytic Leukemia (APL)

• Active extramedullary disease (CNS ≥ CNS2 and/or testicular leukemia) or presence of chloromatous disease

• Receiving concomitant chemotherapy, radiation therapy; immunotherapy or other anti-cancer therapy other than is specified in the protocol

• Systemic fungal, bacterial, viral, or other infection not controlled (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment)

• Pregnant or lactating. The agents used in this study are known to be teratogenic to a fetus and there is no information on the excretion of agents into breast milk. All females of childbearing potential must have a blood test or urine study within 2 weeks prior to registration to rule out pregnancy.

• Known allergy to any of the agents or their ingredients used in this study

• Participating in a concomitant Phase 1 or 2 study

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Nationwide Children's Hospital	Columbus	Ohio	United States	53205
2	American Family Children's Hospital	Madison	Wisconsin	United States	53792
3	Children's Hospital of Wisconsin	Milwaukee	Wisconsin	United States	53226
4	Froedtert Memorial Lutheran Hospital	Milwaukee	Wisconsin	United States	53226

Sponsors and Collaborators

• Medical College of Wisconsin
• American Family Children's Hospital
• Nationwide Children's Hospital

Investigators

• Principal Investigator: Michael J Burke, MD, Medical College of Wisconsin

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Feb 8, 2016
• Informed Consent Form - Sep 12, 2016

More Information

Publications

None provided.

• Responsible Party: Michael Burke, Associate Professor, Medical College of Wisconsin
• ClinicalTrials.gov Identifier: NCT02349178
• Other Study ID Numbers: Bridging
• First Posted: Jan 28, 2015
• Last Update Posted: Mar 9, 2020
• Last Verified: Feb 1, 2020

• Additional relevant MeSH terms: Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Cyclophosphamide; Etoposide; Clofarabine

Study Results

Participant Flow

Arm/Group Title	Bridging Arm
Arm/Group Description	Days 1-5 Receive 20 mg/m2 IV Clofarabine (CLOLAR) over 2 hours followed by 100 mg/m2 IV Etoposide (VP-16, Etopophos) over 2 hours followed by 300 mg/m2 IV Cyclophosphamide (Cytoxan, CTX) as a 30-60 minute infusion Clofarabine: Days 1-5 receive Clofarabine 20 mg/m2 IV over 2 hours Cyclophosphamide: Days 1-5 receive Cyclophosphamide 300 mg/m2 IV as a 30-60 minute infusion Etoposide: Days 1-5 receive Etoposide 100 mg/m2 IV over 2 hours
Period Title: Overall Study
STARTED	6
COMPLETED	6
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Bridging Arm
Arm/Group Description	Days 1-5 Receive 20 mg/m2 IV Clofarabine (CLOLAR) over 2 hours followed by 100 mg/m2 IV Etoposide (VP-16, Etopophos) over 2 hours followed by 300 mg/m2 IV Cyclophosphamide (Cytoxan, CTX) as a 30-60 minute infusion Clofarabine: Days 1-5 receive Clofarabine 20 mg/m2 IV over 2 hours Cyclophosphamide: Days 1-5 receive Cyclophosphamide 300 mg/m2 IV as a 30-60 minute infusion Etoposide: Days 1-5 receive Etoposide 100 mg/m2 IV over 2 hours
Overall Participants	6
Age (Count of Participants)
<=18 years	5 83.3%
Between 18 and 65 years	1 16.7%
>=65 years	0 0%
Sex: Female, Male (Count of Participants)
Female	3 50%
Male	3 50%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	1 16.7%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	5 83.3%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (Count of Participants)
United States	6 100%

Outcome Measures

1. Primary Outcome

Title	Minimal Residual Disease
Description	A bone marrow evaluation to determine study response and remission status will be performed on study Day 30 or upon adequate blood count recovery (ANC > 0.50 and platelet > 50,000), whichever occurs first. If the marrow is hypocellular and without evidence of normal tri-lineage hematopoiesis the marrow should be repeated at Day 42.
Time Frame	Day 30 or adequate blood recovery

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Bridging Arm
Arm/Group Description	Days 1-5 Receive 20 mg/m2 IV Clofarabine (CLOLAR) over 2 hours followed by 100 mg/m2 IV Etoposide (VP-16, Etopophos) over 2 hours followed by 300 mg/m2 IV Cyclophosphamide (Cytoxan, CTX) as a 30-60 minute infusion Clofarabine: Days 1-5 receive Clofarabine 20 mg/m2 IV over 2 hours Cyclophosphamide: Days 1-5 receive Cyclophosphamide 300 mg/m2 IV as a 30-60 minute infusion Etoposide: Days 1-5 receive Etoposide 100 mg/m2 IV over 2 hours
Measure Participants	6
MRD Positive	3 50%
MRD Negative	3 50%

Adverse Events

Time Frame	Up to Day 60 from start of study drug
Arm/Group Title	Bridging Arm
Arm/Group Description	Days 1-5 Receive 20 mg/m2 IV Clofarabine (CLOLAR) over 2 hours followed by 100 mg/m2 IV Etoposide (VP-16, Etopophos) over 2 hours followed by 300 mg/m2 IV Cyclophosphamide (Cytoxan, CTX) as a 30-60 minute infusion Clofarabine: Days 1-5 receive Clofarabine 20 mg/m2 IV over 2 hours Cyclophosphamide: Days 1-5 receive Cyclophosphamide 300 mg/m2 IV as a 30-60 minute infusion Etoposide: Days 1-5 receive Etoposide 100 mg/m2 IV over 2 hours
All Cause Mortality
	Bridging Arm
	Affected / at Risk (%)	# Events
Total	0/6 (0%)
Serious Adverse Events
	Bridging Arm
	Affected / at Risk (%)	# Events
Total	2/6 (33.3%)
Infections and infestations
Sepsis	1/6 (16.7%)	1
Renal and urinary disorders
acute kidney injury	1/6 (16.7%)	1
Other (Not Including Serious) Adverse Events
	Bridging Arm
	Affected / at Risk (%)	# Events
Total	0/6 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.