Brentuximab Vedotin or Crizotinib and Combination Chemotherapy in Treating Patients With Newly Diagnosed Stage II-IV Anaplastic Large Cell Lymphoma
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| ClinicalTrials.gov Identifier: NCT01979536 |
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Recruitment Status :
Active, not recruiting
First Posted : November 8, 2013
Results First Posted : July 6, 2022
Last Update Posted : March 10, 2023
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Sponsor:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
National Cancer Institute (NCI)
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Brief Summary:
This partially randomized phase II trial studies how well brentuximab vedotin or crizotinib and combination chemotherapy works in treating patients with newly diagnosed stage II-IV anaplastic large cell lymphoma. Brentuximab vedotin is a monoclonal antibody, called brentuximab, linked to a toxic agent called vedotin. Brentuximab attaches to CD30 positive cancer cells in targeted way and delivers vedotin to kill them. Crizotinib and methotrexate may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy 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. It is not yet known whether brentuximab vedotin and combination chemotherapy is more effective than crizotinib and combination chemotherapy in treating anaplastic large cell lymphoma.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Anaplastic Large Cell Lymphoma, ALK-Positive Ann Arbor Stage II Noncutaneous Childhood Anaplastic Large Cell Lymphoma Ann Arbor Stage III Noncutaneous Childhood Anaplastic Large Cell Lymphoma Ann Arbor Stage IV Noncutaneous Childhood Anaplastic Large Cell Lymphoma | Drug: Brentuximab Vedotin Drug: Crizotinib Drug: Cyclophosphamide Drug: Cytarabine Drug: Dexamethasone Drug: Doxorubicin Hydrochloride Drug: Etoposide Drug: Ifosfamide Drug: Methotrexate | Phase 2 |
PRIMARY OBJECTIVES:
I. To determine the tolerability of brentuximab vedotin given in combination with standard chemotherapy (anaplastic large cell lymphoma [ALCL]99) and to determine the tolerability of crizotinib given in combination with chemotherapy (ALCL99).
II. To estimate the event free survival (EFS) of Arm brentuximab vedotin (BV) and Arm crizotinib (CZ) and contrast these to historical control data.
SECONDARY OBJECTIVES:
I. To determine the prognostic significance of minimal disseminated disease (MDD) at diagnosis and minimal residual disease (MRD) as measured by real-time (RT)-polymerase chain reaction (PCR) in peripheral blood.
OUTLINE: Patients with body surface area (BSA) < 0.9 m^2 were non-randomly assigned to Arm BV while it was open and were not eligible for the trial while Arm BV was closed. Patients with BSA >= 0.9 m^2 were randomly assigned 1:1 to Arm BV or Arm CZ while both were open and were non-randomly assigned to the open arm while only one of the two arms was open.
ARM BV:
COURSE A (CYCLES 1, 3, AND 5): Patients receive brentuximab vedotin (1.8 mg/dg/dose - Max dose 180 mg) intravenously (IV) over 30 minutes on day 1, dexamethasone orally (PO) twice daily (BID) or IV on days 1-5, ifosfamide IV over 60 minutes on days 1-5, methotrexate IV over 3 hours on day 1, cytarabine IV over 1-30 minutes every 12 hours for 4 doses on days 4 and 5, and etoposide IV over 2 hours on days 4 and 5.
COURSE B (CYCLES 2, 4, AND 6): Patients receive brentuximab vedotin (1.8 mg/dg/dose - Max dose 180 mg), dexamethasone, and methotrexate as in Arm BV, Course A. Patients also receive cyclophosphamide IV over 15-30 minutes on days 1-5 and doxorubicin hydrochloride IV over 1-15 minutes on days 4 and 5.
ARM CZ:
COURSE A (CYCLES 1, 3, AND 5): Patients receive crizotinib (165 mg/m^2) PO BID on days 1-21 and dexamethasone, ifosfamide, methotrexate, cytarabine, and etoposide as in Arm BV, Course A.
COURSE B (CYCLES 2, 4, AND 6): Patients receive crizotinib (165 mg/m^2) PO BID as in Arm CZ, Course A and dexamethasone, cyclophosphamide, methotrexate, and doxorubicin hydrochloride as in Arm BV, Course B.
In all arms, treatment repeats every 21 days for 6 cycles in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 3, 6, 9, 12, 18, 24, 36, 48, and 60 months.
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 137 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| Official Title: | A Randomized Phase 2 Trial of Brentuximab Vedotin (SGN35, NSC# 749710), or Crizotinib (NSC#749005, Commercially Labeled) in Combination With Chemotherapy for Newly Diagnosed Patients With Anaplastic Large Cell Lymphoma (ALCL) |
| Actual Study Start Date : | November 8, 2013 |
| Actual Primary Completion Date : | March 31, 2021 |
Resource links provided by the National Library of Medicine
MedlinePlus related topics:
Lymphoma
| Arm | Intervention/treatment |
|---|---|
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Experimental: Arm BV (brentuximab vedotin, combination chemotherapy)
COURSE A (CYCLES 1, 3, AND 5): Patients receive brentuximab vedotin IV over 30 minutes on day 1, dexamethasone PO BID or IV on days 1-5, ifosfamide IV over 60 minutes on days 1-5, methotrexate IV over 3 hours on day 1, cytarabine IV over 1-30 minutes every 12 hours for 4 doses on days 4 and 5, and etoposide IV over 2 hours on days 4 and 5. COURSE B (CYCLES 2, 4, AND 6): Patients receive brentuximab vedotin, dexamethasone, and methotrexate as in Arm BV, Course A. Patients also receive cyclophosphamide IV over 15-30 minutes on days 1-5 and doxorubicin hydrochloride IV over 1-15 minutes on days 4 and 5. |
Drug: Brentuximab Vedotin
Given IV
Other Names:
Drug: Cyclophosphamide Given IV
Other Names:
Drug: Cytarabine Given IT and IV
Other Names:
Drug: Dexamethasone Given PO or IV
Other Names:
Drug: Doxorubicin Hydrochloride Given IV
Other Names:
Drug: Etoposide Given IV
Other Names:
Drug: Ifosfamide Given IV
Other Names:
Drug: Methotrexate Given IT and IV
Other Names:
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Experimental: Arm CZ (crizotinib, combination chemotherapy)
COURSE A (CYCLES 1, 3, AND 5): Patients receive crizotinib PO BID on days 1-21 and dexamethasone, ifosfamide, methotrexate, cytarabine, and etoposide as in Arm BV, Course A. COURSE B (CYCLES 2, 4, AND 6): Patients receive crizotinib PO BID as in Arm CZ, Course A and dexamethasone, cyclophosphamide, methotrexate, and doxorubicin hydrochloride as in Arm BV, Course B. |
Drug: Crizotinib
Given PO
Other Names:
Drug: Cyclophosphamide Given IV
Other Names:
Drug: Cytarabine Given IT and IV
Other Names:
Drug: Dexamethasone Given PO or IV
Other Names:
Drug: Doxorubicin Hydrochloride Given IV
Other Names:
Drug: Etoposide Given IV
Other Names:
Drug: Ifosfamide Given IV
Other Names:
Drug: Methotrexate Given IT and IV
Other Names:
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Primary Outcome Measures :
- Occurrence of Grade 3+ Non-hematologic Adverse Events [ Time Frame: Up to 60 months ]Will be assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Toxicities will be summarized by individual toxicity counts separated by arm.
- Event Free Survival (EFS) [ Time Frame: Time from study entry until progressive disease, relapse, or death, assessed up to 2 years ]The Kaplan-Meier method will be used to estimate the 2-year EFS for each of the treatment regimens.
Secondary Outcome Measures :
- Prognostic Significance of Minimal Residual Disease [ Time Frame: Baseline up to progressive disease, relapse, or death, assessed up to 2 years ]Analyzed by estimating the 2-year EFS of negative MRD and positive MRD by arm. Minimal disease was performed using serial assessments of the t(2;5)(p23;q35) NPM-ALK fusion transcript using quantitative RT-PCR. Quantitative RT-PCR was performed by extracting total RNA from peripheral blood specimens. Peripheral blood samples were obtained at baseline, on day 1 of cycle 1, and on day 1 of cycle 2. The normalized copy numbers (NCN) were expressed as copy numbers of NPM-ALK per 104 copies of ABL. Minimal disease (MDD) was defined as >10 NCN at baseline.
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| Ages Eligible for Study: | up to 21 Years (Child, Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Criteria
Inclusion Criteria:
- Newly diagnosed patients with histologically proven ALCL (International Classification of Diseases for Oncology [ICD-0] code: 9714/3)
- Disease must be cluster of differentiation (CD)30 positive
- Disease must be anaplastic lymphoma kinase (ALK) positive (defined by local institutional standards)
- Patients must have stage II, III, or IV disease
- Patients must have a life expectancy of >= 8 weeks
- Adequate Liver Function Defined As:
- Total bilirubin =< 1.5 x upper limit of normal (ULN) for age (within 7 days prior to enrollment)
- Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) < 2.5 x upper limit of normal (ULN) for age; for the purpose of this study, the ULN for ALT is 45 U/L (within 7 days prior to enrollment)
- If the lab abnormality is thought to be due to the lymphoma the patient is eligible and dose adjustments should be made
- Adequate Cardiac Function Defined As:
- Shortening fraction of >= 27% by echocardiogram, or
- Ejection fraction of >= 50% by radionuclide angiogram
- Adequate Pulmonary Function Defined As:
- Patients with a history of pulmonary dysfunction must have no evidence of dyspnea at rest, no exercise intolerance due to pulmonary insufficiency, and a pulse oximetry > 92% while breathing room air unless current dysfunction is due to the lymphoma in which case the patient is eligible
Exclusion Criteria:
- Patients with central nervous system (CNS) disease are not eligible
- Patients with disease limited to the skin are not eligible, regardless of how wide-spread
- Patients with stage I disease are not eligible
- Patients who have received any prior cytotoxic chemotherapy for the current diagnosis of ALCL or any cancer diagnosed previously are not eligible
- Previous steroid treatment and/or radiation treatment is not allowed unless it is for the emergent management of a mediastinal mass; emergent steroid treatment and/or radiation treatment should stop once protocol therapy is initiated
- Intrathecal chemotherapy prior to enrollment is allowed for the current diagnosis of ALCL as long as adequate cerebrospinal fluid (CSF) is obtained prior to administration of the intrathecal chemotherapy and subsequently demonstrated to be negative for ALCL
- Female patients who are pregnant are not eligible; pregnancy tests must be obtained in girls who are post menarchal
- Lactating females are not eligible unless they have agreed not to breastfeed their infants
- Sexually active patients of reproductive potential are not eligible unless they agree to use an effective contraceptive method for the duration of treatment and for 3 months after stopping treatment
- Patients with Down syndrome are not eligible due to the amount of methotrexate and potential for side effects
- Patients with an immunodeficiency that existed prior to diagnosis such as primary immunodeficiency syndromes or organ transplant recipients are not eligible
- Cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) substrates with narrow therapeutic indices: Patients chronically receiving medications known to be metabolized by CYP3A4 and with narrow therapeutic indices including pimozide, aripiprazole, triazolam, ergotamine and halofantrine are not eligible; the topical use of these medications (if applicable) is allowed
- CYP3A4 inhibitors: patients chronically receiving drugs that are known potent CYP3A4 inhibitors within 7 days prior to study enrollment, including but not limited to ketoconazole, itraconazole, clarithromycin, erythromycin, ritonavir, indinavir, nelfinavir, saquinavir, delavirdine, nefazodone, diltiazem, verapamil, and grapefruit juice are not eligible; the topical use of these medications (if applicable), e.g. 2% ketoconazole cream, is allowed
- CYP3A4 inducers: patients chronically receiving drugs that are known potent CYP3A4 inducers within 12 days prior to study enrollment, including but not limited to carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, ritonavir, and St. John's wort are not eligible; the topical use of these medications (if applicable) is allowed
- Patients that are known to be positive for human immunodeficiency virus (HIV) are not eligible; note: inclusion of HIV positive patients will be considered at a later date
- Patients who weigh < 10 kg are not eligible
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): NCT01979536
Locations
Show 154 study locations
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
| Principal Investigator: | Eric J Lowe | Children's Oncology Group |
Study Documents (Full-Text)
Documents provided by National Cancer Institute (NCI):
Documents provided by National Cancer Institute (NCI):
Study Protocol and Statistical Analysis Plan [PDF] February 1, 2019
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
| Responsible Party: | National Cancer Institute (NCI) |
| ClinicalTrials.gov Identifier: | NCT01979536 |
| Other Study ID Numbers: |
NCI-2013-02167 NCI-2013-02167 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ) s14-01970 COG-ANHL12P1 ANHL12P1 ( Other Identifier: Children's Oncology Group ) ANHL12P1 ( Other Identifier: CTEP ) U10CA180886 ( U.S. NIH Grant/Contract ) U10CA098543 ( U.S. NIH Grant/Contract ) |
| First Posted: | November 8, 2013 Key Record Dates |
| Results First Posted: | July 6, 2022 |
| Last Update Posted: | March 10, 2023 |
| Last Verified: | March 2023 |
Additional relevant MeSH terms:
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Lymphoma Lymphoma, Non-Hodgkin Lymphoma, Large-Cell, Anaplastic Neoplasms by Histologic Type Neoplasms Lymphoproliferative Disorders Lymphatic Diseases Immunoproliferative Disorders Immune System Diseases Lymphoma, T-Cell Cytarabine Dexamethasone Dexamethasone acetate Cyclophosphamide Ifosfamide |
Isophosphamide mustard Doxorubicin Liposomal doxorubicin Methotrexate Etoposide Etoposide phosphate Brentuximab Vedotin Podophyllotoxin Crizotinib Antineoplastic Agents, Immunological Antibodies Immunoglobulins Antibodies, Monoclonal BB 1101 Immunoconjugates |