Combination Chemotherapy and Ponatinib Hydrochloride in Treating Patients With Acute Lymphoblastic Leukemia
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| ClinicalTrials.gov Identifier: NCT01424982 |
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Recruitment Status :
Recruiting
First Posted : August 29, 2011
Last Update Posted : May 30, 2019
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Sponsor:
M.D. Anderson Cancer Center
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
M.D. Anderson Cancer Center
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Brief Summary:
This phase II trial studies the side effects and how well combination chemotherapy and ponatinib hydrochloride work in treating patients with acute lymphoblastic leukemia. Drugs used in chemotherapy, such as cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride, and dexamethasone, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Ponatinib hydrochloride may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving combination chemotherapy and ponatinib hydrochloride may be an effective treatment for acute lymphoblastic leukemia.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Accelerated Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive Acute Lymphoblastic Leukemia Adult Acute Lymphoblastic Leukemia in Complete Remission B Acute Lymphoblastic Leukemia With t(9;22)(q34.1;q11.2); BCR-ABL1 Blast Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive Philadelphia Chromosome Positive Untreated Adult Acute Lymphoblastic Leukemia | Drug: Cyclophosphamide Drug: Cytarabine Drug: Dexamethasone Drug: Doxorubicin Drug: Doxorubicin Hydrochloride Other: Laboratory Biomarker Analysis Drug: Methotrexate Drug: Ponatinib Drug: Ponatinib Hydrochloride Drug: Prednisone Biological: Rituximab Drug: Vincristine Drug: Vincristine Sulfate | Phase 2 |
PRIMARY OBJECTIVES:
I. To evaluate the clinical efficacy (event-free survival) of an intensive short-term chemotherapy regimen (hyperfractionated cyclophosphamide-vincristine sulfate-Adriamycin [doxorubicin hydrochloride]-dexamethasone [hyper-CVAD] program) given in combination with the tyrosine kinase inhibitor ponatinib hydrochloride (ponatinib) for Philadelphia (Ph)-positive and/or BCR-ABL-positive acute lymphoblastic leukemia (ALL).
II. To evaluate other clinical efficacy endpoints (overall response rate and survival) and safety of the regimen.
OUTLINE:
ODD CYCLES (1, 3, 5, and 7): Patients receive cyclophosphamide intravenously (IV) over 3 hours every 12 hours on days 1-3, doxorubicin hydrochloride IV continuously over 24 hours on day 4, vincristine sulfate IV over 30 minutes on days 1 and 11, dexamethasone IV over 30 minutes or orally (PO) once daily (QD) on days 1-4 and 11-14, and ponatinib hydrochloride PO QD on days 1-14 of cycle 1 and continuously in cycles 3, 5, and 7. Patients with CD20 expression may also receive rituximab IV on days 1 and 11 of cycle 1 and 3. Treatment repeats every 3-4 weeks for up to 8 cycle in the absence of disease progression or unacceptable toxicity.
EVEN CYCLES (2, 4, 6, and 8): Patients receive methotrexate IV over 24 hours on day 1, ponatinib hydrochloride PO QD continuously, and cytarabine IV over 3 hours every 12 hours on days 2 and 3. Patients with CD20 expression may also receive rituximab IV on days 1 and 8 of cycle 2 and 4. Treatment repeats every 3-4 weeks for up to 8 cycle in the absence of disease progression or unacceptable toxicity.
MAINTENANCE THERAPY: Patients receive vincristine sulfate IV on day 1, prednisone PO daily on days 1-5, and ponatinib hydrochloride PO QD on days 1-28. Cycle repeat every 28 days for 24 months in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 30 days and then every 6 months for up to 24 months.
| Study Type : | Interventional (Clinical Trial) |
| Estimated Enrollment : | 100 participants |
| Intervention Model: | Single Group Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| Official Title: | Phase II Study of Combination of Hyper-CVAD and Ponatinib in Patients With Philadelphia (PH) Chromosome Positive and/or BCR-ABL Positive Acute Lymphoblastic Leukemia (ALL) |
| Actual Study Start Date : | October 5, 2011 |
| Estimated Primary Completion Date : | October 31, 2020 |
| Estimated Study Completion Date : | October 31, 2020 |
Resource links provided by the National Library of Medicine
| Arm | Intervention/treatment |
|---|---|
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Experimental: Treatment (combination chemotherapy, ponatinib hydrochloride)
See Detailed Description.
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Drug: Cyclophosphamide
Given IV
Other Names:
Drug: Cytarabine Given IV
Other Names:
Drug: Dexamethasone Given IV or PO
Other Names:
Drug: Doxorubicin Given IV
Other Names:
Drug: Doxorubicin Hydrochloride Given IV
Other Names:
Other: Laboratory Biomarker Analysis Correlative studies Drug: Methotrexate Given IV
Other Names:
Drug: Ponatinib Given PO
Other Names:
Drug: Ponatinib Hydrochloride Given PO
Other Names:
Drug: Prednisone Given PO
Other Names:
Biological: Rituximab Given IV
Other Names:
Drug: Vincristine Given IV
Other Names:
Drug: Vincristine Sulfate Given IV
Other Names:
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Primary Outcome Measures :
- Event-free survival [ Time Frame: The time from the start of the treatment until any failure (resistant disease, relapse, or death), assessed up to 24 months ]Kaplan-Meier survival curves will be constructed.
Secondary Outcome Measures :
- Complete response rate [ Time Frame: Up to 24 months after completion of study treatment ]Complete response is defined as achieving bone marrow blasts =< 5% AND platelets >= 100 AND absolute neutrophil count >= 1000 within 3 courses of treatment. The method of Thall, Simon, and Estey will be employed to perform short-term interim efficacy. Response rate and its corresponding 95% confidence interval will be provided at the end of the study.
- Incidence of grade 3-4 toxicity according to the M.D. Anderson Leukemia-specific Adverse Event Recording and Reporting Guidelines [ Time Frame: Up to 24 months ]The method of Thall, Simon, and Estey will be employed to perform short-term interim safety monitoring. Will be summarized in frequency tables or in the form of mean, standard deviation, and range where appropriate. Toxicity rate and its corresponding 95% confidence interval will be provided at the end of the study.
- Overall survival [ Time Frame: Up to 24 months after completion of study treatment ]Kaplan-Meier survival curves will be constructed. Survival rates at specific time points will be estimated along with corresponding 95% confidence intervals.
- Disease-specific survival [ Time Frame: Up to 24 months after completion of study treatment ]Kaplan-Meier survival curves will be constructed. Survival rates at specific time points will be estimated along with corresponding 95% confidence intervals.
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| Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Criteria
Inclusion Criteria:
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Diagnosis of one of the following:
- Previously untreated Ph-positive ALL (either t[9;22] and/or bcr-abl positive) (includes patients initiated on first course of hyper-CVAD before cytogenetics known) or with lymphoid accelerated or blast phase chronic myelogenous leukemia (CML)
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Previously treated Ph-positive ALL or CML (in accelerated phase or blast phase), after 1-2 courses of chemotherapy with or without other tyrosine kinase inhibitors (TKIs)
- If they achieved complete response (CR), they are assessable only for event-free and overall survival, or
- If they failed to achieve CR, they are assessable for CR, event-free, and overall survival
- Performance status =< 2 (Eastern Cooperative Oncology Group [ECOG] scale)
- Total serum bilirubin =< 1.5 x upper limit of normal (ULN), unless due to Gilbert's syndrome
- Alanine aminotransferase (ALT) =< 2 x ULN
- Aspartate aminotransferase (AST) =< 2.5 x ULN
- Serum lipase and amylase =< 1.5 x ULN
- For females of childbearing potential, a negative pregnancy test must be documented prior to randomization
- Female and male patients who are fertile must agree to use an effective form of contraception with their sexual partners from randomization through 4 months after the end of treatment
- Adequate cardiac function as assessed clinically by history and physical examination
- Signed informed consent
Exclusion Criteria:
- Active serious infection not controlled by oral or intravenous antibiotics
- Known active hepatitis B; patients with chronic hepatitis B who are on appropriate viral suppressive therapy may be allowed after discussion with the principal investigator (PI)
- History of acute pancreatitis within 1 year of study or history of chronic pancreatitis
- History of alcohol abuse
- Uncontrolled hypertriglyceridemia (triglycerides > 450 mg/dL)
- Active secondary malignancy other than skin cancer (e.g., basal cell carcinoma or squamous cell carcinoma) that in the investigator's opinion will shorten survival to less than 1 year
- Active grade III-V cardiac failure as defined by the New York Heart Association criteria
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Clinically significant, uncontrolled, or active cardiovascular disease, specifically including, but not restricted to:
- Any history of myocardial infarction (MI), stroke, or revascularization
- Unstable angina or transient ischemic attack prior to enrollment
- Congestive heart failure prior to enrollment, or left ventricular ejection fraction (LVEF) less than lower limit of normal per local institutional standards prior to enrollment
- Diagnosed or suspected congenital long QT syndrome
- Any history of clinically significant atrial or ventricular arrhythmias (such as atrial fibrillation, ventricular tachycardia, ventricular fibrillation, or torsades de pointes) as determined by the treating physician
- Prolonged corrected QT (QTc) interval on pre-entry electrocardiogram (> 470 msec) unless corrected after electrolyte replacement
- Any history of venous thromboembolism including deep venous thrombosis or pulmonary embolism
- Uncontrolled hypertension (diastolic blood pressure > 90 mmHg; systolic > 140 mmHg); patients with hypertension should be under treatment on study entry to effect blood pressure control
- Patients currently taking drugs that are generally accepted to have a risk of causing torsades de pointes (unless these can be changed to acceptable alternatives)
- Taking any medications or herbal supplements that are known to be strong inhibitors of cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) within at least 14 days before the first dose of ponatinib
- Prior history of treatment with ponatinibfor > 1 month; patient who has been treated with ponatinib for 1 month prior starting the treatment is eligible
- Treatment with any investigational antileukemic agents or chemotherapy agents in the last 7 days before study entry, unless full recovery from side effects has occurred or patient has rapidly progressive disease judged to be life-threatening by the investigator; patient who has been treated with ponatinib for 1 month prior starting the treatment is eligible
- Pregnant and lactating women will not be eligible; women of childbearing potential should have a negative pregnancy test prior to entering on the study and be willing to practice methods of contraception; women do not have childbearing potential if they have had a hysterectomy or are postmenopausal without menses for 12 months; in addition, men enrolled on this study should understand the risks to any sexual partner of childbearing potential and should practice an effective method of birth control
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History of significant bleeding disorder unrelated to cancer, including:
- Diagnosed congenital bleeding disorders (e.g., von Willebrand's disease)
- Diagnosed acquired bleeding disorder within one year (e.g., acquired anti-factor VIII antibodies)
- Patients with documented significant pleural or pericardial effusions unless they are thought to be secondary to their leukemia
Information from the National Library of Medicine
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01424982
Contacts
| Contact: Elias Jabbour | 713-792-7026 | ejabbour@mdanderson.org |
Locations
| United States, Texas | |
| M D Anderson Cancer Center | Recruiting |
| Houston, Texas, United States, 77030 | |
| Contact: Elias Jabbour 713-792-7026 | |
| Principal Investigator: Elias Jabbour | |
Sponsors and Collaborators
M.D. Anderson Cancer Center
National Cancer Institute (NCI)
Investigators
| Principal Investigator: | Elias Jabbour | M.D. Anderson Cancer Center |
Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
| Responsible Party: | M.D. Anderson Cancer Center |
| ClinicalTrials.gov Identifier: | NCT01424982 History of Changes |
| Other Study ID Numbers: |
2011-0030 NCI-2011-02941 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ) 2011-0030 ( Other Identifier: M D Anderson Cancer Center ) P30CA016672 ( U.S. NIH Grant/Contract ) |
| First Posted: | August 29, 2011 Key Record Dates |
| Last Update Posted: | May 30, 2019 |
| Last Verified: | May 2019 |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
Additional relevant MeSH terms:
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Leukemia Precursor Cell Lymphoblastic Leukemia-Lymphoma Leukemia, Lymphoid Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive Leukemia, Myeloid, Accelerated Phase Blast Crisis Philadelphia Chromosome Neoplasms by Histologic Type Neoplasms Lymphoproliferative Disorders Lymphatic Diseases Immunoproliferative Disorders Immune System Diseases Myeloproliferative Disorders |
Bone Marrow Diseases Hematologic Diseases Translocation, Genetic Chromosome Aberrations Pathologic Processes Cell Transformation, Neoplastic Carcinogenesis Neoplastic Processes Cytarabine Dexamethasone Prednisone Cortisone Dexamethasone acetate Cyclophosphamide Rituximab |