Pegaspargase and Combination Chemotherapy in Treating Patients With Newly Diagnosed Acute Lymphoblastic Leukemia

• Sponsor: OHSU Knight Cancer Institute (Other)
• Overall Status: Terminated
• CT.gov ID: NCT01005914
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 11
• Location: 1
• Arm: 1
• Duration (Months): 59
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

RATIONALE: Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more cancer cells.

PURPOSE: This phase II trial is studying the side effects of giving pegaspargase together with combination chemotherapy and to see how well it works in treating patients with newly diagnosed acute lymphoblastic leukemia.

Condition or Disease	Intervention/Treatment	Phase
Leukemia	Drug: cyclophosphamide; Drug: cytarabine; Drug: dexamethasone; Drug: doxorubicin hydrochloride; Drug: imatinib mesylate; Drug: methotrexate; Drug: methylprednisolone; Drug: pegaspargase; Drug: vincristine sulfate	Phase 2

Detailed Description

OBJECTIVES:

Primary

• To estimate the complete response rate in patients with newly diagnosed acute lymphoblastic leukemia treated with pegaspargase in combination with hyper-CVAD regimen comprising cyclophosphamide, dexamethasone, vincristine sulfate, doxorubicin hydrochloride, methotrexate, and cytarabine.

• To determine the safety and tolerability of this regimen in these patients.

Secondary

• To evaluate the progression-free survival and overall survival of patients treated with this regimen.

• To determine the half-life of pegaspargase when administered in combination with hyper-CVAD regimen.

• To monitor the development of neutralizing antibodies to pegaspargase when administered in combination with hyper-CVAD regimen.

• To assess minimal residual disease by flow cytometry at the end of courses 1A and 1B.

OUTLINE: This is a multicenter study.

• Hyper-CVAD regimen (courses 1, 3, 5, and 7): Patients receive cyclophosphamide IV over 2-3 hours twice daily on days 1-3, dexamethasone IV on days 1-4 and 11-14, methotrexate intrathecally (IT) on day 2, doxorubicin hydrochloride IV over 2 hours and pegaspargase IV over 1-2 hours on day 4, vincristine sulfate IV on days 4 and 11, and cytarabine IT on day 8.

• High-dose methotrexate/cytarabine regimen (courses 2, 4, 6, and 8): Patients receive methotrexate IV continuously over 24 hours on day 1, methylprednisolone IV twice daily on days 1-3, methotrexate IT on day 2, cytarabine IV over 2 hours twice daily on days 2 and 3, pegaspargase IV over 1-2 hours on day 3, and cytarabine IT on day 8.

Treatment repeats every 3-4 weeks for 8 courses in the absence of disease progression or unacceptable toxicity. Patients with Philadelphia chromosome-positive disease also receive oral imatinib mesylate daily beginning at diagnosis.

Patients who complete 8 courses of chemotherapy and are not candidates for hematopoietic stem cell transplantation receive maintenance therapy off study.

Blood samples are collected at baseline and periodically during study for pharmacokinetics and neutralizing antibody assays.

After completion of study therapy, patients are followed up every 6 months.

Study Design

• Study Type: Interventional
• Actual Enrollment: 11 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Trial of the Addition of PEG-Asparaginase to the Hyper-CVAD Regimen in Adult Newly-Diagnosed Acute Lymphoblastic Leukemia
• Study Start Date: Jun 1, 2009
• Actual Primary Completion Date: Mar 1, 2013
• Actual Study Completion Date: May 1, 2014

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Group 1 Drug:cyclophosphamide Day 1- 3: 300 m g/m2 IV over 2-3 hours every 12 hours for 6 doses plus mesna 600 mg/ m2 /day continuous infusion Days 1-3 Drug:cytarabine Day 2 & 3: 3g/m2 IV over 2 hours q12 X 4 Drug:dexamethasone Day 1-4; 11-14: 40 mg daily Drug:doxorubicin hydrochloride Day 4: 50 mg/m2 IV over 2 hours Drug:imatinib mesylate 600 mg/day Drug:methotrexate Day 1: 1g/ m2 (200 mg/ m2load IV over 2 hours plus 800 mg/ m2 over 22 hours as an infusion Drug: methylprednisolone Day 1-3: 50mg IV BID Drug: pegaspargase Day 3/Day4: 2,500 IU/ m2 IV Drug: vincristine sulfate Day 4 & 11: 2 mg IV

Drug: cyclophosphamide; Day 1- 3: 300 m g/m2 IV over 2-3 hours every 12 hours for 6 doses plus mesna 600 mg/ m2 /day continuous infusion Days 1-3; Other Names: Cytoxan, Neosar, CTX ; Drug: cytarabine; Day 2 & 3: 3g/m2 IV over 2 hours q12 X 4; Other Names: Cytosar-U, Ara-C, Arabinosylcytosine ; Drug: dexamethasone; Day 1-4; 11-14: 40 mg daily; Other Names: Decadron, DexPak, dex ; Drug: doxorubicin hydrochloride; Day 4: 50 mg/m2 IV over 2 hours; Other Names: Adriamycin RDF, Adriamycin PFS ; Drug: imatinib mesylate; 600 mg/day; Other Names: Gleevec, Glivec ; Drug: methotrexate; Day 1: 1g/ m2 (200 mg/ m2load IV over 2 hours plus 800 mg/ m2 over 22 hours as an infusion; Other Names: Trexall, Rheumatrex, MTX ; Drug: methylprednisolone; Day 1-3: 50mg IV BID; Other Names: Medrol, Depo-Medrol, Solu-Medrol ; Drug: pegaspargase; Day 3/Day4: 2,500 IU/ m2 IV; Other Names: Onscapar, PEG-L-asparaginase ; Drug: vincristine sulfate; Day 4 & 11: 2 mg IV; Other Names: Marqibo

Outcome Measures

Primary Outcome Measures

1. Complete Response Rate After Course 1 of Pegaspargase When Administered in Combination With Hyper-CVAD Regimen [After day 4 of treatment]

   The complete response rate after 1A cycle of a PEG-Asparaginase and hyper-CVAD combination regimen will be estimated, and an exact 95% confidence interval will be computed using a binomial distribution.

2. Grade 3 and 4 Toxicity Associated With the Combination of Peg-Asparaginase and Hyper-CVAD Which Include: Allergic Reactions, Elevated Liver Enzymes, Hyperbilirubinemia, Hyperglycemia, Central Nervous System (CNS) Thrombosis, and Pancreatitis. [The assessment of safety will be based mainly on the frequency of adverse events]

Secondary Outcome Measures

1. 2-year Progression-free Survival [After completion of 8 cycles]

2. Proportion of Patients Who Achieve Complete Response or Partial Response After Courses 1 and 2 [An interim analysis of safety is planned after the enrollment of 15 evaluable patients.]

3. Overall Survival [At least every 6 months until death.]

4. Rate of Minimal Residual Disease [End of cycles 1A and 1B]

   Cycle 1A: Days 1 through 14 Cycle 1B: Days 1 through 8, after the first 14 days of cycle 1A

5. Half-life of Pegaspargase [The approximate t½ in adult patients is 5.73 days. The half-life is independent of the dose administered, disease status, renal or hepatic function, age, or gender.]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 60 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients must be newly diagnosed (untreated) with Acute Lymphoblastic Leukemia based on a bone marrow examination unless there is a contraindication to having the test performed. This includes precursor-B ALL, precursor-T ALL, and Philadelphia chromosome positive ALL. For reference, see criteria by Center for International Blood and Marrow Transplant Research (CIBMTR).> 20% blasts on a bone marrow aspirate OR If a bone marrow aspirate is not obtained, the diagnosis of acute leukemia can be established by a pathologic diagnosis of acute leukemia on a bone marrow biopsy OR A complete blood count documenting the presence of at least 10,000 white blood cells (WBC)/μl and at least 20% circulating blasts

• Adults, 18 to 60 years of age.

• Women of child bearing potential (WOCBP) must be willing to use adequate contraception to avoid pregnancy for the duration of study participation.

• Eastern Cooperative Oncology Group (ECOG) performance status < 2

• Adequate renal function defined as: Serum creatinine ≤ 2.0 x upper limit normal (ULN) for institution

• Adequate hepatic function defined as:Total bilirubin ≤ 2.0 x ULN for institution Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.0 x ULN for institution

• Patient must have the ability to understand and the willingness to sign a written informed consent document. The patient and/or the patient's legally authorized guardian must acknowledge consent for treatment as a human subject on this study.

Exclusion Criteria:

• Mature B (Burkitt's) ALL will be excluded.

• An active malignancy other than ALL (with the exception of basal and/or squamous cell skin cancers and curatively treated carcinoma of the cervix) within 5 past years of study entry.

• Documented central nervous system (CNS) involvement with leukemia will be excluded. A diagnostic lumbar puncture will not be part of screening procedures.

• Severe pulmonary, renal, or hepatic disease not related to the patient's ALL will be excluded.

• Cardiac dysfunction as defined by:Myocardial infarction within the last 6 months of study entry, or Reduced left ventricular function with an ejection fraction ≤50% as measured by Multigated Acquisition (MUGA) scan or echocardiogram at study entry, Unstable angina, Unstable cardiac arrhythmias, New York Heart Association (NYHA) Class III or IV heart failure, Electrocardiographic evidence of acute ischemia or active conduction system abnormalities

• Known or suspected human immunodeficiency virus (HIV)-positive patients are excluded from the study because of possible risk of lethal infection when treated with marrow suppressive therapy.

• Any concurrent severe and/or uncontrolled medical condition (e.g. uncontrolled diabetes, infection, hypertension, etc.) or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol.

• Patients who have had chemotherapy or radiotherapy for ALL prior to entering the study will be excluded. Hydroxyurea and one dose of intravenous vincristine are allowed prior to registration for patient convenience. Prior steroid therapy is allowable, ≤5 days prior to the start of the regimen.

• Patients may not have received any other investigational agents within the last 30 days.

• WOCBP who are unwilling or unable to use an acceptable method of contraception for the entire study period. Pregnant or lactating women are excluded from this study because of possible risk to the fetus or infant. Women with a positive serum pregnancy test on enrollment or prior to study drug administration will be excluded.

• Men whose sexual partners are WOCBP, who are unwilling or unable to use an acceptable contraceptive method to avoid pregnancy of his partner for the entire study period.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	OHSU Knight Cancer Institute	Portland	Oregon	United States	97239

Sponsors and Collaborators

• OHSU Knight Cancer Institute
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Brandon Hayes-Lattin, OHSU Knight Cancer Institute

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: OHSU Knight Cancer Institute
• ClinicalTrials.gov Identifier: NCT01005914
• Other Study ID Numbers: CDR0000642363; P30CA069533; OHSU-4913; ENZON-OHSU-4913
• First Posted: Nov 1, 2009
• Last Update Posted: Mar 4, 2015
• Last Verified: Feb 1, 2015

• Keywords provided by OHSU Knight Cancer Institute: adults; Philadelphia chromosome precursor ALL,; T-cell ALL; untreated ALL
• Additional relevant MeSH terms: Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Cytarabine; Dexamethasone; Methylprednisolone; Methylprednisolone Acetate; Methylprednisolone Hemisuccinate; Cyclophosphamide; Doxorubicin; Liposomal doxorubicin; Methotrexate; Vincristine; Imatinib Mesylate; Asparaginase; Pegaspargase

Study Results

Participant Flow

Arm/Group Title	Group 1
Arm/Group Description	Drug:cyclophosphamide-Day 1- 3: 300 m g/m2 IV over 2-3 hours every 12 hours for 6 doses plus mesna 600 mg/ m2 /day continuous infusion Days 1-3 Drug:cytarabine Day 2 & 3: 3g/m2 IV over 2 hours q12 X 4 Drug:dexamethasone Day 1-4; 11-14: 40 mg daily Drug:doxorubicin hydrochloride Day 4: 50 mg/m2 IV over 2 hours Drug:imatinib mesylate 600 mg/day Drug:methotrexate Day 1: 1g/ m2 (200 mg/ m2load IV over 2 hours plus 800 mg/ m2 over 22 hours as an infusion Drug: methylprednisolone Day 1-3: 50mg IV BID Drug: pegaspargase Day 3/Day4: 2,500 IU/ m2 IV Drug: vincristine sulfate Day 4 & 11: 2 mg IV cyclophosphamide: Day 1- 3: 300 m g/m2 IV over 2-3 hours every 12 hours for 6 doses plus mesna 600 mg/ m2 /day continuous infusion Days 1-3 cytarabine: Day 2 & 3: 3g/m2 IV over 2 hours q12 X 4 dexamethasone: Day 1-4; 11-14: 40 mg daily doxorubicin hydrochloride: Day 4: 50 mg/m2 IV over 2 hours imatinib mesylate: 600 mg/day methotrexate: D
Period Title: Overall Study
STARTED	11
COMPLETED	1
NOT COMPLETED	10

Baseline Characteristics

Arm/Group Title	Group 1
Arm/Group Description	Drug:cyclophosphamide Day 1- 3: 300 m g/m2 IV over 2-3 hours every 12 hours for 6 doses plus mesna 600 mg/ m2 /day continuous infusion Days 1-3 Drug:cytarabine Day 2 & 3: 3g/m2 IV over 2 hours q12 X 4 Drug:dexamethasone Day 1-4; 11-14: 40 mg daily Drug:doxorubicin hydrochloride Day 4: 50 mg/m2 IV over 2 hours Drug:imatinib mesylate 600 mg/day Drug:methotrexate Day 1: 1g/ m2 (200 mg/ m2load IV over 2 hours plus 800 mg/ m2 over 22 hours as an infusion Drug: methylprednisolone Day 1-3: 50mg IV BID Drug: pegaspargase Day 3/Day4: 2,500 IU/ m2 IV Drug: vincristine sulfate Day 4 & 11: 2 mg IV cyclophosphamide: Day 1- 3: 300 m g/m2 IV over 2-3 hours every 12 hours for 6 doses plus mesna 600 mg/ m2 /day continuous infusion Days 1-3 cytarabine: Day 2 & 3: 3g/m2 IV over 2 hours q12 X 4 dexamethasone: Day 1-4; 11-14: 40 mg daily doxorubicin hydrochloride: Day 4: 50 mg/m2 IV over 2 hours imatinib mesylate: 600 mg/day methotrexate: D
Overall Participants	11
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	42.9
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	11 100%
>=65 years	0 0%
Sex: Female, Male (Count of Participants)
Female	5 45.5%
Male	6 54.5%
Region of Enrollment (participants) [Number]
United States	11 100%

Outcome Measures

1. Primary Outcome

Title	Complete Response Rate After Course 1 of Pegaspargase When Administered in Combination With Hyper-CVAD Regimen
Description	The complete response rate after 1A cycle of a PEG-Asparaginase and hyper-CVAD combination regimen will be estimated, and an exact 95% confidence interval will be computed using a binomial distribution.
Time Frame	After day 4 of treatment

Outcome Measure Data

Analysis Population Description

Outcome Measure analysis was not performed due to early termination of the study due to safety concerns

Arm/Group Title	Group 1
Arm/Group Description	Cy D1- 3: 300 m g/m2 IV- 6 doses, mesna 600 mg/ m2 /day continuous IV D 1-3, ARAC D 2 & 3: 3g/m2 IV q12 X 4, Dex D1-4; 11-14: 40 mg daily, doxorubicin hydrochloride D4: 50 mg/m2 IV, imatinib mesylate 600 mg/day, MTX D1: 1g/ m2 200 mg/ m2 load IV plus 800 mg/ m2, methylprednisolone D 1-3: 50mg IV BID, pegaspargase D3/D4: 2,500 IU/ m2 IV, vincristine sulfate D4 & 11: 2 mg IV, Cy: D 1- 3: 300 m g/m2 IV 6 doses plus mesna 600 mg/ m2 /day, continuous infusion D 1-3. ARAC D 2 & 3: 3g/m2 IV q12 X 4, dex: D 1-4; 11-14: 40 mg daily, doxorubicin hydrochloride: D 4: 50 mg/m2 IV, imatinib mesylate: 600 mg/day, MTX: D 1: 1g/ m2 200 mg/ m2load IV plus 800 mg/ m2 IV, methylprednisolone: D 1-3: 50mg IV BID, pegaspargase: D 3/D4: 2,500 IU/ m2 IV, vincristine sulfate: D 4 & 11: 2 mg IV, pharmacological study: C1A: pre-dose between Days 1 to 4, C1A: D11 or 12., C1A: D18 or 19, C 1A: D25 or 26, C1A: D32 or 33 C1B: pre-dose between D1-3, C1B: D1 or 11 C1B: D17 or 18, C1B: D24 or 25 C1B: D31 or 32
Measure Participants	0

2. Primary Outcome

Title	Grade 3 and 4 Toxicity Associated With the Combination of Peg-Asparaginase and Hyper-CVAD Which Include: Allergic Reactions, Elevated Liver Enzymes, Hyperbilirubinemia, Hyperglycemia, Central Nervous System (CNS) Thrombosis, and Pancreatitis.
Time Frame	The assessment of safety will be based mainly on the frequency of adverse events

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

3. Secondary Outcome

Title	2-year Progression-free Survival
Time Frame	After completion of 8 cycles

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

4. Secondary Outcome

Title	Proportion of Patients Who Achieve Complete Response or Partial Response After Courses 1 and 2
Time Frame	An interim analysis of safety is planned after the enrollment of 15 evaluable patients.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

5. Secondary Outcome

Title	Overall Survival
Time Frame	At least every 6 months until death.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

6. Secondary Outcome

Title	Rate of Minimal Residual Disease
Description	Cycle 1A: Days 1 through 14 Cycle 1B: Days 1 through 8, after the first 14 days of cycle 1A
Time Frame	End of cycles 1A and 1B

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

7. Secondary Outcome

Title	Half-life of Pegaspargase
Time Frame	The approximate t½ in adult patients is 5.73 days. The half-life is independent of the dose administered, disease status, renal or hepatic function, age, or gender.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	All unexpected adverse events (AEs) related, probably related or possibly related to the study drug which are equal or greater than Grade 3 and serious adverse events (SAEs) were collected from first patient enrollment on 10/21/09 through 2010.
Adverse Event Reporting Description	Adverse events collected: Unexpected AEs (when type or severity isn't listed in Expected AE List) Deaths within 30 days of drug admin. Grade ≥ 3 (related to the following): Allergic reactions CNS thrombosis/embolism Coagulopathy Elevated AST, ALT Hyperbilirubinemia Hyperglycemia Hypertriglyceridemia Pancreatitis
Arm/Group Title	Group 1
Arm/Group Description	cyclophosphamide D1- 3: 300 m g/m2 IV 6 doses plus mesna 600 mg/ m2 /day cont. IV D1-3, cytarabine D2 & 3: 3g/m2 IV, dexD1-4; 11-14: 40 mg daily, doxorubicin hydrochloride D4: 50 mg/m2 IV Drug:imatinib mesylate 600 mg/day Drug:methotrexate Day 1: 1g/ m2 (200 mg/ m2load IV over 2 hours plus 800 mg/ m2 over 22 hours as an infusion Drug: methylprednisolone Day 1-3: 50mg IV BID Drug: pegaspargase Day 3/Day4: 2,500 IU/ m2 IV Drug: vincristine sulfate Day 4 & 11: 2 mg IV cyclophosphamide: Day 1- 3: 300 m g/m2 IV over 2-3 hours every 12 hours for 6 doses plus mesna 600 mg/ m2 /day continuous infusion Days 1-3 cytarabine: Day 2 & 3: 3g/m2 IV over 2 hours q12 X 4 dexamethasone: Day 1-4; 11-14: 40 mg daily doxorubicin hydrochloride: Day 4: 50 mg/m2 IV over 2 hours imatinib mesylate: 600 mg/day methotrexate: D
All Cause Mortality
	Group 1
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Group 1
	Affected / at Risk (%)	# Events
Total	9/11 (81.8%)
Blood and lymphatic system disorders
neutropenic fever	4/11 (36.4%)	7
hypokalemia, hyponatremia	1/11 (9.1%)	2
Cardiac disorders
Chest pain	1/11 (9.1%)	1
Cardiac Arrest	1/11 (9.1%)	1
Gastrointestinal disorders
Abdominal pain	1/11 (9.1%)	1
gastoenteritis	1/11 (9.1%)	1
General disorders
Death	1/11 (9.1%)	1
Immune system disorders
anaphylaxis	1/11 (9.1%)	1
Infections and infestations
Bacillus species sepsis with encephalitis	1/11 (9.1%)	1
Septic shock	2/11 (18.2%)	2
fungemia, staph bacteremia	1/11 (9.1%)	1
gnr bacteremia	1/11 (9.1%)	1
acute epiglottitis	1/11 (9.1%)	1
klebsiella bacteremia	1/11 (9.1%)	1
pneumonia (streptoccocus bacteremia)	1/11 (9.1%)	1
lung infection (fungal)	1/11 (9.1%)	1
alpha-hemolytic streptococcal bacteremia	1/11 (9.1%)	1
Vascular disorders
Pulmonary embolism	1/11 (9.1%)	1
Other (Not Including Serious) Adverse Events
	Group 1
	Affected / at Risk (%)	# Events
Total	0/11 (0%)

Limitations/Caveats

Early termination of the study due to adverse events.

More Information

Certain Agreements

All Principal Investigators ARE 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.