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NCT01979536 · CITED IN SOURCE DOCUMENTS

Brentuximab Vedotin or Crizotinib and Combination Chemotherapy in Treating Patients With Newly Diagnosed Stage II-IV Anaplastic Large Cell Lymphoma

An NCI or FDA source cites this study. A citation does not establish that it applies to an individual diagnosis.

Phase
PHASE2
Status at capture
COMPLETED
Registry last update
2024-04-30

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.

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What did the study report?

Outcomes, safety and baseline populations are separate source sections. Quality-of-life measures appear under their original outcome titles.

flow

Participant flow

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baseline

Baseline characteristics

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outcome · POSTED

Occurrence of Grade 3+ Non-hematologic Adverse Events

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outcome · POSTED

Event Free Survival (EFS)

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outcome · POSTED

Prognostic Significance of Minimal Residual Disease

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adverse events

Adverse events

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more info

Limitations, agreements, and source contact

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Who could take part
eligibility 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
healthy Volunteers
false
maximum Age
21 Years
sex
ALL
std Ages
  1. CHILD
  2. ADULT
Treatment arms and interventions
arm Groups
  1. description
    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.
    intervention Names
    1. Drug: Brentuximab Vedotin
    2. Drug: Cyclophosphamide
    3. Drug: Cytarabine
    4. Drug: Dexamethasone
    5. Drug: Doxorubicin Hydrochloride
    6. Drug: Etoposide
    7. Drug: Ifosfamide
    8. Drug: Methotrexate
    label
    Arm BV (brentuximab vedotin, combination chemotherapy)
    type
    EXPERIMENTAL
  2. description
    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.
    intervention Names
    1. Drug: Crizotinib
    2. Drug: Cyclophosphamide
    3. Drug: Cytarabine
    4. Drug: Dexamethasone
    5. Drug: Doxorubicin Hydrochloride
    6. Drug: Etoposide
    7. Drug: Ifosfamide
    8. Drug: Methotrexate
    label
    Arm CZ (crizotinib, combination chemotherapy)
    type
    EXPERIMENTAL
interventions
  1. arm Group Labels
    1. Arm BV (brentuximab vedotin, combination chemotherapy)
    description
    Given IV
    name
    Brentuximab Vedotin
    other Names
    1. ADC SGN-35
    2. Adcetris
    3. Anti-CD30 Antibody-Drug Conjugate SGN-35
    4. Anti-CD30 Monoclonal Antibody-MMAE SGN-35
    5. Anti-CD30 Monoclonal Antibody-Monomethylauristatin E SGN-35
    6. cAC10-vcMMAE
    7. SGN-35
    type
    DRUG
  2. arm Group Labels
    1. Arm CZ (crizotinib, combination chemotherapy)
    description
    Given PO
    name
    Crizotinib
    other Names
    1. MET Tyrosine Kinase Inhibitor PF-02341066
    2. PF-02341066
    3. PF-2341066
    4. PF02341066
    5. Xalkori
    type
    DRUG
  3. arm Group Labels
    1. Arm BV (brentuximab vedotin, combination chemotherapy)
    2. Arm CZ (crizotinib, combination chemotherapy)
    description
    Given IV
    name
    Cyclophosphamide
    other Names
    1. (-)-Cyclophosphamide
    2. 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate
    3. Asta B 518
    4. B-518
    5. Carloxan
    6. Ciclofosfamida
    7. Ciclofosfamide
    8. Cicloxal
    9. Clafen
    10. Claphene
    11. CP monohydrate
    12. CTX
    type
    DRUG
  4. arm Group Labels
    1. Arm BV (brentuximab vedotin, combination chemotherapy)
    2. Arm CZ (crizotinib, combination chemotherapy)
    description
    Given IT and IV
    name
    Cytarabine
    other Names
    1. .beta.-Cytosine arabinoside
    2. 1-.beta.-D-Arabinofuranosyl-4-amino-2(1H)pyrimidinone
    3. 1-.beta.-D-Arabinofuranosylcytosine
    4. 1-Beta-D-arabinofuranosyl-4-amino-2(1H)pyrimidinone
    5. 1-Beta-D-arabinofuranosylcytosine
    6. 1.beta.-D-Arabinofuranosylcytosine
    7. 2(1H)-Pyrimidinone, 4-Amino-1-beta-D-arabinofuranosyl-
    8. 2(1H)-Pyrimidinone, 4-amino-1.beta.-D-arabinofuranosyl-
    9. Alexan
    10. Ara-C
    11. ARA-cell
    12. Arabine
    type
    DRUG
  5. arm Group Labels
    1. Arm BV (brentuximab vedotin, combination chemotherapy)
    2. Arm CZ (crizotinib, combination chemotherapy)
    description
    Given PO or IV
    name
    Dexamethasone
    other Names
    1. Aacidexam
    2. Adexone
    3. Aknichthol Dexa
    4. Alba-Dex
    5. Alin
    6. Alin Depot
    7. Alin Oftalmico
    8. Amplidermis
    9. Anemul mono
    10. Auricularum
    11. Auxiloson
    12. Baycadron
    type
    DRUG
  6. arm Group Labels
    1. Arm BV (brentuximab vedotin, combination chemotherapy)
    2. Arm CZ (crizotinib, combination chemotherapy)
    description
    Given IV
    name
    Doxorubicin Hydrochloride
    other Names
    1. 5,12-Naphthacenedione, 10-[(3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy]-7,8, 9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-, hydrochloride, (8S-cis)- (9CI)
    2. ADM
    3. Adriacin
    4. Adriamycin
    5. Adriamycin Hydrochloride
    6. Adriamycin PFS
    7. Adriamycin RDF
    8. ADRIAMYCIN, HYDROCHLORIDE
    9. Adriamycine
    10. Adriblastina
    11. Adriblastine
    12. Adrimedac
    type
    DRUG
  7. arm Group Labels
    1. Arm BV (brentuximab vedotin, combination chemotherapy)
    2. Arm CZ (crizotinib, combination chemotherapy)
    description
    Given IV
    name
    Etoposide
    other Names
    1. Demethyl Epipodophyllotoxin Ethylidine Glucoside
    2. EPEG
    3. Lastet
    4. Toposar
    5. Vepesid
    6. VP 16
    7. VP 16-213
    8. VP 16213
    9. VP-16
    10. VP-16-213
    11. VP16
    type
    DRUG
  8. arm Group Labels
    1. Arm BV (brentuximab vedotin, combination chemotherapy)
    2. Arm CZ (crizotinib, combination chemotherapy)
    description
    Given IV
    name
    Ifosfamide
    other Names
    1. Asta Z 4942
    2. Asta Z-4942
    3. Cyfos
    4. Holoxan
    5. Holoxane
    6. Ifex
    7. IFO
    8. IFO-Cell
    9. Ifolem
    10. Ifomida
    11. Ifomide
    12. Ifosfamidum
    type
    DRUG
  9. arm Group Labels
    1. Arm BV (brentuximab vedotin, combination chemotherapy)
    2. Arm CZ (crizotinib, combination chemotherapy)
    description
    Given IT and IV
    name
    Methotrexate
    other Names
    1. Abitrexate
    2. Alpha-Methopterin
    3. Amethopterin
    4. Brimexate
    5. CL 14377
    6. CL-14377
    7. Emtexate
    8. Emthexat
    9. Emthexate
    10. Farmitrexat
    11. Fauldexato
    12. Folex
    type
    DRUG
Study design
allocation
RANDOMIZED
intervention Model
PARALLEL
masking Info
masking
NONE
primary Purpose
TREATMENT
Enrollment
count
137
type
ACTUAL
Registered outcome plans (not posted results)
primary Outcomes
  1. description
    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.
    measure
    Occurrence of Grade 3+ Non-hematologic Adverse Events
    time Frame
    Up to 60 months
  2. description
    The Kaplan-Meier method will be used to estimate the 2-year EFS for each of the treatment regimens.
    measure
    Event Free Survival (EFS)
    time Frame
    Time from study entry until progressive disease, relapse, or death, assessed up to 2 years
secondary Outcomes
  1. description
    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.
    measure
    Prognostic Significance of Minimal Residual Disease
    time Frame
    Baseline up to progressive disease, relapse, or death, assessed up to 2 years
Full study description
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.
detailed Description
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.
Source references
references
  1. citation
    Lowe EJ, Reilly AF, Lim MS, Gross TG, Saguilig L, Barkauskas DA, Wu R, Alexander S, Bollard CM. Crizotinib in Combination With Chemotherapy for Pediatric Patients With ALK+ Anaplastic Large-Cell Lymphoma: The Results of Children's Oncology Group Trial ANHL12P1. J Clin Oncol. 2023 Apr 10;41(11):2043-2053. doi: 10.1200/JCO.22.00272. Epub 2022 Dec 19.
    pmid
    36534942
    type
    DERIVED
  2. citation
    Lowe EJ, Reilly AF, Lim MS, Gross TG, Saguilig L, Barkauskas DA, Wu R, Alexander S, Bollard CM. Brentuximab vedotin in combination with chemotherapy for pediatric patients with ALK+ ALCL: results of COG trial ANHL12P1. Blood. 2021 Jul 1;137(26):3595-3603. doi: 10.1182/blood.2020009806.
    pmid
    33684925
    type
    DERIVED
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        iatric patients with NSCLC. In a study that evaluated XALKORI in combination with chemotherapy in pediatric patients with newly diagnosed ALCL (Study ANHL12P1; NCT01979536), 13 of 66 (20%) patients had a Grade 2 or higher thromboembolic event, including pulmonary embolism in 6%. The safety and effectiveness of XALKORI in combinat
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        (small cell/lymphohistiocytic) were the two factors significantly associated with inferior outcome.</li><li>The <a href="/clinicaltrials/NCT01979536">ANHL12P1 (NCT01979536)</a> study evaluated the addition of either brentuximab vedotin or crizotinib to ALCL99 trial chemotherapy. The study confirmed the poor prognosis associated w
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      source update dates
      1. context
        Updated: April 17, 2025
        datetime
        2025-04-17T12:00:00Z
        display
        April 17, 2025
    3. release id
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      edge id
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      requested nct id
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      primary nct id
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      source kind
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      source url
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      2. NDA202570
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      occurrences
      1. context exact
        iatric patients with NSCLC. In a study that evaluated XALKORI in combination with chemotherapy in pediatric patients with newly diagnosed ALCL (Study ANHL12P1; NCT01979536), 13 of 66 (20%) patients had a Grade 2 or higher thromboembolic event, including pulmonary embolism in 6%. The safety and effectiveness of XALKORI in combinat
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      source url
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      primary nct id
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      source kind
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      payload
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      link basis
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      occurrences
      1. context exact
        e, methotrexate, cyclophosphamide, doxorubicin) administered every 21 days for a total of 6 cycles was assessed but have not been established based on a study (NCT01979536) in 67 patients, which included 61 pediatric patients age 2 to less than 17 years with newly diagnosed ALK+ ALCL. No new safety signals were identified in this
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      source kind
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      payload sha256
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      payload
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      clinical indication matching status
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      occurrences
      1. context exact
        e, methotrexate, cyclophosphamide, doxorubicin) administered every 21 days for a total of 6 cycles was assessed but have not been established based on a study (NCT01979536) in 67 patients, which included 61 pediatric patients age 2 to less than 17 years with newly diagnosed ALK+ ALCL. No new safety signals were identified in this
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    Preserved source evidence · Not medical advice