54179060LYM3003, A Randomized, Open-label, Safety and Efficacy Study of Ibrutinib in Pediatric and Young Adult Patients With Relapsed or Refractory Mature B-cell non-Hodgkin Lymphoma
Study ID: STU 042017-061
This is a 2-part multicenter study. a safety and pharmacokinetic run-in part (Part 1) will be conducted before starting the randomized part (Part 2) of the study. Part 2 is a randomized, open-label, Phase 3 study to compare the safety and efficacy of ibrutinib in combination with chemoimmunotherapy (CiT) (RiCe (rituximab, ifosfamide, carboplatin, etoposide, and dexamethasone) or RViCi (rituximab, vincristine, ifosfamide, carboplatin, idarubicin, and dexamethasone)) versus CiT alone in children and young adult subjects with relapsed or refractory mature B-cell non-Hodgkin lymphoma (nHL). Subjects who are 1 to 30 years old at the time of relapse (but with primary nHL diagnosis at age of [Less Than]18 years old) will be eligible. at this site, the RiCe regimen (and not RViCi) will be used. Part 1 up to 24 pediatric patients (ages 1 to less than 18 years) will be entered into Part 1. at least the first 2 patients in each age group (1-5 years, 6-11 years and 12-17 years) will enter Part 1. all patients in Part 1 will receive a standard chemotherapy regimen, RiCe together with ibrutinib. The first 2 patients in each of the age groups will receive a lower dose of ibrutinib (240 mg/m2) during Cycle 1. if there are no concerns about this dose during Cycle 1, then the dose for future cycles for these patients will be increased. if there are some questions about this dose during Cycle 1, then the dose for future cycles for these patients may stay the same or be lowered. after the first 2 patients, additional patients of each age group may be recruited in Part 1 in order to obtain enough information to decide on the correct dose for patients in that age group. once the optimal dose for an age group has been decided, all future patients in that age group will receive ibrutinib from Cycle 1 onwards at that dose. The study doctor will confirm what dose patients entering Part 1 will receive. Part 2 approximately 72 additional patients aged 1 to 30 years will be entered into Part 2. Part 2 will only open in each age group when enough information has been obtained from Part 1. all patients in Part 2 will be assigned by chance to one of two groups: * RiCe standard chemotherapy + ibrutinib * RiCe standard chemotherapy only neither participants nor the researchers will be allowed to choose which group participants are assigned to. Participants' chance of getting RiCe therapy plus ibrutinib is 2 out of every 3. Participants' chance of getting RiCe therapy alone is 1 out of every 3.
1. 1 to < 18 years of age (Part 1 only), or 1 to 30 years of age, inclusive, if initial diagnosis of mature B-cell non-Hodgkin lymphoma (NHL) occurred at < 18 years of age (Part 2 only) 2. Relapsed/refractory Burkitt lymphoma (BL), Burkitt-like lymphoma (BLL), Burkitt leukemia (ie, B-AL) with FAB3 morphology or presence of surface immunoglobulin by flow cytometry, diffuse large B-cell lymphoma (DLBCL), DLBCL not otherwise specified (NOS), or other pediatric mature B-cell NHL NOTE: Must have pathology report for the original NHL diagnosis or from the time of relapse (if available). If these pathology reports are not available, the pathology results of a fresh biopsy will be required for enrollment into the study. 3. Must be in first recurrence or have disease that is primarily refractory to conventional therapy 4. Must have at least 1 of the following: a) 1 site of measurable disease > 1 cm in the longest diameter and > 1 cm in the shortest diameter by radiological imaging b) bone marrow involvement c) cerebrospinal fluid with blasts present 5. Lansky-Karnofsky score of >= 50 6. Adequate organ function defined as follows: a) Absolute neutrophil count (ANC) >= 500 cells/mm3. Growth factor support per institutional guidelines is permitted during the Screening and Treatment phases. b) Platelets >= 50,000 cells/mm3. Subjects with thrombocytopenia due to bone marrow infiltration are eligible if platelets are >= 25,000 cells/mm3. Transfusion support is permitted during the Screening and Treatment phases. c) Alanine aminotransferase <= 3 x upper limit of normal (ULN) d) Aspartate aminotransferase <= 3 x ULN e) Total bilirubin < 1.5 x ULN, except in subjects with Gilbert syndrome or in subjects in whom the bilirubin rise is of non-hepatic origin f) Serum creatinine < 2 x ULN for age or glomerular filtration rate > 30 mL/min/1.73 m2 by the CKiD Schwartz equation 7. Must have recovered from the acute toxic effects of prior chemotherapy, immunotherapy, or radiotherapy, in the opinion of the investigator, prior to entering this study hematologic toxicities must meet the above criteria 8. Informed Consent Form (ICF) must be signed by legally authorized representative or by the subject if at legal age of consent indicating understanding of the purpose of, and procedures required for, the study and willingness to participate in the study. Assent is also required of children capable of understanding the nature of the study per country-specific or site-specific standards as described in the protocol. 9. Adolescent women/young women of childbearing potential must have a negative highly sensitive serum or urine B-human chorionic gonadotropin (B-hCG) pregnancy test at Screening before enrollment/randomization. Adolescent/young women who are pregnant or breastfeeding are ineligible for this study. 10. Adolescents/young women of childbearing potential must be practicing a highly effective method of contraception (failure rate of <1% per year when used consistently and correctly) and agree to remain on a highly effective method throughout the study and for at least 3 months after the last dose of ibrutinib and 1 year after the last dose of the background chemoimmunotherapy (CIT), whichever is later. Examples of highly effective contraceptives include - user-independent methods: implantable progestogen-only hormone contraception associated with inhibition of ovulation; intrauterine device (IUD); intrauterine hormone-releasing system (IUS); vasectomized partner; sexual abstinence (sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study drug. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of the subject). - user-dependent methods: combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulation: oral, intravaginal, and transdermal; progestogen-only hormone contraception associated with inhibition of ovulation: oral and injectable; a barrier method of contraception (eg, condom with spermicidal foam/gel/film/cream/suppository). Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent with local regulations regarding the use of contraceptive methods for subjects participating in clinical studies. Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the efficacy of the contraceptive method. Women of child bearing potential must use highly effective contraceptive measures while taking IMBRUVICA. Those using hormonal methods of birth control must add a barrier method (eg, condom with spermicidal foam/gel/film/cream/suppository). Note: If the childbearing potential changes after start of the study (eg, a premenarchal woman experiences menarche) or the risk of pregnancy changes (eg, a woman who is not heterosexually active becomes active,) a woman must begin a highly effective method of contraception, as described throughout the inclusion criteria. 11. During the study and for a minimum of 1 spermatogenesis cycle (defined as approximately 90 days) after receiving the last dose of study drug, in addition to the user-independent highly effective method of contraception, a man - who is sexually active with a woman of childbearing potential must agree to use a barrier method of contraception (eg, condom with spermicidal foam/gel/film/cream/suppository) - who is sexually active with a woman who is pregnant must use a condom - must agree not to donate sperm 12. Must be willing and able to adhere to the prohibitions and restrictions specified in this protocol
- Cancer Related
- Healthy Volunteers
- UT Southwestern Principal Investigator
- MARTHA MARIE PACHECO
JANSSEN RESEARCH AND DEVELOPMENT LLC
Run-in Part (Part 1) objectives Primary Confirm that the pharmacokinetics in pediatric subjects is consistent with that in adults Secondary - evaluate the safety and tolerability of ibrutinib in combination with RiCe (rituximab, ifosfamide, carboplatin, etoposide, and dexamethasone) or RViCi (rituximab, vincristine, ifosfamide, carboplatin, idarubicin, and dexamethasone) background therapy in pediatric subjects with B-cell malignancies - assess anti-tumor activity of ibrutinib as add-on to RiCe or RViCi regimens - assess disease-specific biomarkers - assess the pharmacodynamic response - acceptability and palatability assessment of all ibrutinib formulations exploratory - evaluate other response biomarkers - explore the exposure-response relationships Randomized Part (Part 2) objectives Primary * assess efficacy (event-free survival (eFS)) of ibrutinib in combination with RiCe or RViCi background therapy compared to RiCe or RViCi background therapy alone Secondary * evaluate the safety and tolerability of ibrutinib in combination with RiCe or RViCi background therapy in pediatric subjects and young adults with B-cell malignancies * Determine the overall response rate (oRR) * evaluate tumor volume reduction at Day 14 * Determine the number and proportion of subjects who proceed to stem cell transplantation * evaluate the time to response * Measure the duration of response * evaluate long-term survival (eFS at 2 and 3 years) * evaluate overall survival * assess disease-specific biomarkers * assess the pharmacodynamic response, if deemed appropriate based on Part 1 results * assess the population pharmacokinetics of ibrutinib in pediatric subjects and young adults * acceptability and palatability assessment of all ibrutinib formulations exploratory * evaluate other response biomarkers * explore the exposure-response relationships Long-term survival for patients with relapsed or refractory Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL) is poor, with only 10% to 20% of these patients surviving beyond 2 years, underscoring the unmet medical need in this patient population. ibrutinib is an oral agent with an acceptable safety profile and novel mechanism of action. The drug inhibits the B-cell receptor pathway via Bruton's tyrosine kinase (BTK) inhibition, thereby overcoming the B-cell receptor (BCR)- and chemokine-controlled retention of malignant B cells in their supportive microenvironments. it has been shown to disrupt the pathogenesis of several B-cell malignancies. Therefore, the addition of ibrutinib to a salvage regimen like RiCe/RViCi may provide some advantages for the pediatric population given its non-overlapping mechanism of action and toxicity profile.