Clinical Trials /

Ibrutinib, Rituximab, and Consolidation Chemotherapy in Treating Young Patients With Newly Diagnosed Mantle Cell Lymphoma

NCT02427620

Description:

This phase II trial studies how well ibrutinib, rituximab, and consolidation chemotherapy consisting of cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride, dexamethasone, methotrexate, and cytarabine work in treating young patients with newly diagnosed mantle cell lymphoma. Ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as rituximab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride, dexamethasone, methotrexate, and cytarabine, 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. Giving more than one drug (combination chemotherapy) may kill more cancer cells. Giving ibrutinib together with rituximab and consolidation chemotherapy may be a better treatment for mantle cell lymphoma.

Related Conditions:
  • Mantle Cell Lymphoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Study of Ibrutinib Plus Rituximab With Hyper-CVAD Consolidation in Newly Diagnosed Young Patients With Mantle Cell Lymphoma
  • Official Title: A Phase II Study of Ibrutinib Plus Rituximab With Hyper-CVAD Consolidation in Newly Diagnosed Young Patients With Mantle Cell Lymphoma: A Window Period for Bioimmunotherapy Before Chemotherapy

Clinical Trial IDs

  • ORG STUDY ID: 2014-0559
  • SECONDARY ID: NCI-2015-00960
  • NCT ID: NCT02427620

Conditions

  • Lymphoma

Interventions

DrugSynonymsArms
IbrutinibPCI-32765, ImbruvicaIbrutinib + Rituximab with Hyper-CVAD Consolidation
RituximabRituxanIbrutinib + Rituximab with Hyper-CVAD Consolidation
CyclophosphamideCytoxan, NeosarIbrutinib + Rituximab with Hyper-CVAD Consolidation
DexamethasoneDecadronIbrutinib + Rituximab with Hyper-CVAD Consolidation
MesnaMesnexIbrutinib + Rituximab with Hyper-CVAD Consolidation
VincristineIbrutinib + Rituximab with Hyper-CVAD Consolidation
DoxorubicinDoxorubicin hydrochloride, Adriamycin PFS, Adriamycin RDF, Adriamycin, RubexIbrutinib + Rituximab with Hyper-CVAD Consolidation
G-CSFFilgrastim, NeupogenIbrutinib + Rituximab with Hyper-CVAD Consolidation
MethotrexateIbrutinib + Rituximab with Hyper-CVAD Consolidation
CytarabineAra-C, Cytosar, DepoCyt, Cytosine arabinosine hydrochlorideIbrutinib + Rituximab with Hyper-CVAD Consolidation
CitrovorumLeucovorin, WellcovorinIbrutinib + Rituximab with Hyper-CVAD Consolidation

Purpose

The goal of this clinical research study is to learn if a combination of ibrutinib and rituximab plus the combination of 2 different intensive chemotherapy regimens can help to control MCL. The safety of this drug combination will also be studied.

Detailed Description

Study Drug Administration:

This study will have 2 Parts.

If you are found to be eligible for this study, you will begin Part 1 of the study.

At any time you may be given other drugs to help prevent or decrease side effects, such as nausea and vomiting. You may ask the study staff for information about how the drugs are given and their risks.

Part 1:

Part 1 will last up to 12 cycles. Each cycle is 28 days.

Every day you will take 4 ibrutinib capsules with about 1 cup (8 ounces) of water. You must take all 4 capsules at about the same time every day, at least 30 minutes before or at least 2 hours after eating a meal. Do not open the capsules or dissolve them.

If you miss a dose, you can take it up to 6 hours after the time you would have taken it. If it is later than 6 hours, you should skip the dose and start taking the capsules at the same time as usual the next day.

You will need to fill out diary cards with information about when you take ibrutinib. You should bring the diary cards with you to appointments.

On Days 1, 8, 15, and 22 of Cycle 1, you will receive rituximab by vein. The first dose should take about 6-8 hours. After that, each dose should take about 4 hours.

You will then receive rituximab by vein over 4 hours on Day 1 of Cycles 3-12. You will not receive the drug in Cycle 2.

For some patients, you may receive the rituximab dose over 2 days. Your doctor will tell you if this is best for you.

You will be checked every 2 cycles to learn how you may be responding. Based on your response, you may start Part 2 of the study.

Part 2:

During part 2, depending on your response in Part 1, you will receive 2 alternating combinations of drugs (the first combination in the first cycle, then the second combination in the second cycle, and so on) for 2-8 cycles. Each cycle will be 28 days.

First combination:

You will receive the following drugs during the odd-numbered cycles (Cycles 1, 3, 5, and 7) of Part 2:

- Rituximab by vein over 6 hours on Day 1

- Dexamethasone either by mouth or by vein on Days 1-4

- Cyclophosphamide by vein (over 3 hours each time) 2 times each day on Days 2-4

- Mesna by vein non-stop on Days 2-4

- Doxorubicin by vein over 15-30 minutes on Day 5

- Vincristine by vein over 15-30 minutes on Day 5

To help prevent infections, you will also receive Filgrastim (G-CSF) injections just under your skin, starting at 24-36 hours after the end of the doxorubicin infusion. You will continue to receive these injections every day until your white blood cell counts recover.

Second combination:

You will receive the following drugs during the even-numbered cycles (Cycles 2, 4, 6, and 8) of Part 2:

- Rituximab by vein over 6 hours on Day 1

- Methotrexate by vein over 24 hours on Day 2

- Cytarabine by vein (over 2 hours each time) 2 times each day on Days 3-4

When you receive methotrexate, you will also be given leucovorin by mouth to help prevent side effects. Blood (about 1 tablespoon) will be drawn 24 and 48 hours after the end of the methotrexate infusion so that the study doctor can learn when it is best to stop giving you leucovorin.

You will again receive G-CSF after doxorubicin until your white blood cell counts recover.

Study Visits in Part 1:

On Day 1 of every cycle:

- You will have a physical and neurological exam.

- Blood (about 2 tablespoons) will be drawn for routine tests and to check the status of the disease.

- If you can become pregnant, you will have a blood (about 1½ tablespoons) or urine pregnancy test.

- If your doctor thinks it is needed, you will have a bone marrow biopsy and/or aspiration to check the status of the disease.

- If the study doctor thinks it is needed, you will have a gastrointestinal endoscopy.

- If the study doctor thinks it is needed, you will have a PET/CT scan to check the status of the disease.

On Days 8, 15, and 22 of Cycle 1, you will have a physical exam.

On Day 1 of every odd-numbered cycle (Cycles 3, 5, 7, and so on), if the study doctor thinks it is needed, you will have a CT scan to check the status of the disease.

If your CT scan shows that the disease has gotten better, you will have a PET/CT scan at the end of Part 1.

If the doctor thinks it is needed based on the results of your screening bone marrow biopsy and/or colonoscopy, these tests will be repeated at the end of Part 1.

Study Visits in Part 2:

On Day 1 of every cycle:

- You will have a physical and neurological exam.

- You will have an EKG.

- Blood (about 2 tablespoons) will be drawn for routine tests and to check the status of the disease.

- If you can become pregnant, you will have a blood (about 1½ tablespoons) or urine pregnancy test.

Up to 3 times a week from Days 8-28 of all Cycles, you will have a blood (about 2 tablespoons each time) drawn for routine tests.

At the end of Cycles 2, 4, 6, and 8, and then every 3-6 cycles after that, you will have a CT scan and chest x-ray to check the status of the disease.

Length of Treatment:

You may continue taking the study drugs in Part 1 for up to 12 cycles. You may continue taking the study drugs in Part 2 for up to 8 cycles. You will no longer be able to take the drugs if the disease gets worse, if intolerable side effects occur, or if you are unable to follow study directions.

End-of-Treatment Visit:

After you finish taking the study drugs:

- You will have a physical and neurological exam.

- Blood (about 2 tablespoons) will be drawn for routine tests and to check the status of the disease.

- If your doctor thinks it is needed, you will have a PET/CT scan and/or bone marrow biopsy/aspiration to check the status of the disease.

- If your doctor thinks it is needed, you will have a gastrointestinal endoscopy.

- If you can become pregnant, you will have a blood (about 1½ tablespoons) or urine pregnancy test.

Long Term Follow-Up:

After your end-of-treatment visit and if the disease has not gotten worse, you will return for a clinic visit every 4 months for 2 years, then every 6 months for 2 years, and then every year after that to see how you are doing. At these visits:

- Blood (about 2 tablespoons) will be drawn for routine tests and to check the status of the disease.

- You will have a PET/CT scan to check the status of the disease.

This is an investigational study. Ibrutinib is FDA approved and commercially available for the treatment of patients with MCL. Rituximab is FDA approved for the treatment of non-Hodgkin's lymphoma and certain types of leukemia. Using these 2 drugs in combination with each other is investigational. All of the drugs in Part 2 are standard of care for the treatment of lymphoma.

Up to 100 participants will be enrolled in this study. All will take part at MD Anderson.

Trial Arms

NameTypeDescriptionInterventions
Ibrutinib + Rituximab with Hyper-CVAD ConsolidationExperimentalIn Part 1, participants receive the combination of Ibrutinib and Rituximab. Depending on participant's response in Part 1, they will receive 2 alternating combinations of drugs (the first combination in the first cycle, then the second combination in the second cycle, and so on) for 2-8 cycles. Each cycle will be 28 days. In Part 2, participants are consolidated with Rituximab plus Cyclophosphamide, Vincristine, Doxorubicin, and Dexamethasone (Hyper-CVAD) alternating every 28 days with Rituximab plus high-dose Methotrexate-Cytarabine (MTX-AraC).
  • Ibrutinib
  • Rituximab
  • Cyclophosphamide
  • Dexamethasone
  • Mesna
  • Vincristine
  • Doxorubicin
  • G-CSF
  • Methotrexate
  • Cytarabine
  • Citrovorum

Eligibility Criteria

Inclusion Criteria:

1. Patient has a confirmed diagnosis of mantle cell lymphoma with B-lymphocyte antigen CD20 (CD20) positivity in tissue biopsy.

2. Patients with MCL must be symptomatic and need immediate therapy. Symptoms and nature of MCL include any of the following: a) blastoid variant, b) pleomorphic variant, c) B symptoms, d) Mantle Cell International Prognostic Score (MIPI) > 3, e) Antigen KI-67 (ki67) > 30%, f) bulky tumors > 5 cm, g) disease threatening organ function, h) elevated Lactate Dehydrogenase (LDH), i) peripheral blood white blood cell (PB WBC) > 50,000, j) pancytopenia due to bone marrow MCL, k) patient's choice due to anxiety; l) pain due to lymphoma.

3. Patient has newly diagnosed disease with no prior therapy.

4. Understand and voluntarily sign an IRB-approved informed consent form.

5. Age >/= 18 to </= 65 years at the time of signing the informed consent.

6. Patients should have bi-dimensional measurable disease using the Cheson criteria (Measureable disease by CT scan defined as at least 1 lesion that measures =/>1.5 cm in single dimension.) Gastrointestinal or bone marrow or spleen only patients are allowable.

7. Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less

8. An absolute neutrophil count (ANC) > 1,000/mm^3 and platelet count >100,000/mm^3 (Patients who have bone marrow infiltration by MCL are eligible if their ANC is >/= 500/mm^3 [growth factor allowed] or their platelet level is equal to or > than 20,000/mm^3. These patients should be discussed with either the principal investigator (PI) or Co-PI of the study for final approval).

9. Serum bilirubin <1.5 mg/dl and Cr Clearance >/= 30 mL/min, Aspartate transaminase (AST)/ serum glutamic oxaloacetic transaminase (SGOT) and Alanine transaminase (ALT)/ serum glutamic-pyruvic transaminase (SGPT) < 2 x upper limit of normal or < 5 x upper limit of normal if hepatic metastases are present. Gilbert's disease is allowed.

10. Cardiac ejection fraction >/= 50% by Echocardiogram (ECHO) or multiple gated acquisition scan (MUGA).

11. Disease free of prior malignancies with exception of currently treated basal cell, squamous cell carcinoma of the skin, carcinoma "in situ" of the cervix or breast, or other malignancies in remission (including prostate cancer patients in remission from radiation therapy, surgery or brachytherapy), not actively being treated.

12. Females of childbearing potential (FCBP)* must have a negative serum or urine pregnancy test (within 30 days of initiation of protocol therapy) and must be willing to use acceptable methods of birth control. Men must agree to use a latex condom during sexual contact with a female of childbearing potential even if they have had a successful vasectomy. *A female of childbearing potential is a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months).

Exclusion Criteria:

1. Any serious medical condition including but not limited to, uncontrolled hypertension, uncontrolled diabetes mellitus, active/symptomatic coronary artery disease, chronic obstructive pulmonary disease (COPD), renal failure, active hemorrhage, or psychiatric illness that, in the investigators opinion places the patient at unacceptable risk and would prevent the subject from signing the informed consent form.

2. Pregnant or breast feeding females.

3. Known human immunodeficiency virus (HIV) infection.

4. Patients with active Hepatitis B or C infection (not including patients with prior Hepatitis B vaccination.) These patients should be cleared by gastrointestinal (GI) consultation for Hepatitis B and Infectious Disease consult for Hepatitis C.

5. All patients with central nervous system lymphoma.

6. Significant neuropathy (Grades 3 - 4, or Grade 2 with pain) within 14 days prior to enrollment.

7. Contraindication to any of the required concomitant drugs or supportive treatments or intolerance to hydration due to preexisting pulmonary or cardiac impairment including pleural effusion requiring thoracentesis or ascites requiring paracentesis unless due to lymphoma.

8. Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel or ulcerative colitis, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction, or any other gastrointestinal condition that could interfere with the absorption and metabolism of ibrutinib.

9. Major surgery within 4 weeks of initiation of therapy. Clearance letter from primary physician required.

10. Requires anticoagulation with warfarin or equivalent vitamin K antagonist.

11. Requires treatment with strong Cytochrome P4503A (CYP3A) inhibitors

12. Patients with New York Heart Association (NYHA) Class III and IV heart failure, myocardial infarction in the preceding 6 months, and significant conduction abnormalities, including but not limited to 2nd degree atrioventricular block (AV block) type II, 3rd degree block, QT prolongation (QTc > 500 msec), sick sinus syndrome, ventricular tachycardia, symptomatic bradycardia (heart rate < 50 bpm), hypotension, light headedness and syncope. Patients with persistent and uncontrolled atrial fibrillation will be excluded. The protocol excludes patients who have recently had a stent and by recommendation of their cardiologist need to stay on anticoagulants such as warfarin or equivalent vitamin K antagonist.

13. Acute infection requiring treatment (IV antibiotics, antivirals, or antifungals) within 14 days prior to initiation of study.

Maximum Eligible Age:65 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall Response
Time Frame:8 weeks
Safety Issue:
Description:Overall response (OR) defined as complete response (CR) + partial response (PR). OR monitored using the Bayesian stopping boundaries calculated based on beta-binomial distribution.

Secondary Outcome Measures

Measure:Progression Free Survival (PFS) of Ibrutinib plus Rituximab with Rituximab - Cyclophosphamide, Vincristine, Doxorubicin, and Dexamethasone (Hyper-CVAD)
Time Frame:56 days
Safety Issue:
Description:Response definitions for measurable disease from the Revised Response Criteria for Malignant Lymphoma used. Complete response (CR) defined as complete disappearance of all detectable clinical evidence of disease and disease-related symptoms if present before therapy. Participant considered to have stable disease (SD) when they fail to attain the criteria needed for a CR or PR, but do not fulfill those for progressive disease.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:M.D. Anderson Cancer Center

Trial Keywords

  • Lymphoma
  • Mantle cell lymphoma
  • MCL
  • B-lymphocyte antigen
  • CD20
  • Ibrutinib
  • PCI-32765
  • Imbruvica
  • Rituximab
  • Rituxan
  • Cyclophosphamide
  • Cytoxan
  • Neosar
  • Vincristine
  • Mesna
  • Mesnex
  • Dexamethasone
  • Decadron
  • Doxorubicin
  • Doxorubicin hydrochloride
  • Adriamycin PFS
  • Adriamycin RDF
  • Adriamycin
  • Rubex
  • G-CSF
  • Filgrastim
  • Neupogen
  • Methotrexate
  • Cytarabine
  • Ara-C
  • Cytosar
  • DepoCyt
  • Cytosine arabinosine hydrochloride
  • Citrovorum
  • Leucovorin
  • Wellcovorin

Last Updated

March 3, 2017