Primary• To assess the safety profile and determine the pediatric maximum tolerated dose and/or recommended phase 2 dose of brentuximab vedotin• To assess the pharmacokinetics of brentuximab vedotin• To determine the overall response rate (complete…
ID
Source
Brief title
Condition
- Lymphomas Hodgkin's disease
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary Endpoints
• Adverse events (AEs), serious adverse events (SAEs), assessments of clinical
laboratory values, and vital sign measurements
• Plasma concentrations of brentuximab vedotin, total therapeutic antibody, and
MMAE
• Overall response rate (CR, PR) as determined by an IRF using PET, CT, and
clinical assessment according to IWG revised response criteria
Secondary outcome
Secondary Endpoints
• Anti-therapeutic antibody (ATA) titer and neutralizing ATA titer
• Overall response rate (CR, PR) as determined by an independent review
facility (IRF) using positron emission tomography (PET), computed tomography
(CT), and clinical assessment, according to International Working Group (IWG)
revised response criteria
• Time to progression
• Time to response
• Duration of response
• Event-free survival
• Progression-free survival
• Overall survival
Adverse events, serious adverse events, assessments of clinical laboratory
values, and vital sign measurements
• Plasma concentrations of brentuximab vedotin, total therapeutic antibody, and
MMAE
• Anti-therapeutic antibody (ATA) titer and neutralizing ATA titer
Exploratory Endpoints
• Immune reconstitution (enumeration of the total lymphocyte count and
lymphocyte subsets, total immunoglobulin and IgG, IgM, IgA levels, levels of
the antibodies to tetanus, HiB, and polioserotypes) at baseline, end of
treatment, and 6- and 12-months post-last dose.
Background summary
Classical Hodgkin lymphoma (HL) is defined histopathologically by the presence
of malignant Hodgkin-Reed-Sternberg (H/RS) cells in a background of
inflammatory cells. H/RS cells are characterized by the expression of CD30, a
surface tumor marker and cell membrane protein belonging to the tumor necrosis
factor (TNF) receptor superfamily. HL occurs in patients in all age groups and
presents a bimodal distribution with peaks at 15 to 35 years of age and over
the age of 60. The median age at diagnosis is 38 years in adults and 13.5 years
in the pediatric population. The disease is very uncommon in children under 4
years of age and almost nonexistent in those under 2 years of age.
Painless cervical lymphadenopathy is the most common presenting sign (> 70%)(5)
in children with HL, often with a fluctuating course leading to a delay in
diagnosis. Mediastinal masses are frequent (about 60% of pediatric patients)
and sometimes discovered after routine chest X-rays. Patients with mediastinal
adenopathy may present with respiratory symptoms such as shortness of breath,
chest pain, or cough. Fewer than 5% present with disease limited to the upper
cervical lymph nodes, above the level of the hyoid bone. Disseminated
lymphadenopathy is rare in patients with HL.
Approximately 25% of patients will have systemic B symptoms at presentation (as
defined by the Ann Arbor system), typically fatigue, fever, weight loss, and
night sweats. Pruritus and intermittent fever usually associated with night
sweats are classic symptoms of HL. The frequency of these symptoms increases
with advanced stage of the disease. Accurate disease staging and classification
of the histological subtype determine the most favorable treatment options and
prognosis. The stage of the disease is assigned according to the Ann Arbor
staging system with Cotswold modifications for HL. All cases are subclassified
to indicate the absence (A) or presence (B) of the systemic symptoms at
presentation. Pediatric patients are more likely than adults to present with
stage I/II disease and less likely to present with stage IV disease.
Adolescents are more likely to have B symptoms than pediatric patients younger
than 10 years and have a much higher
relapse rate.
Transplantation-related mortality rates of more than 20% and even higher
relapse rates in pediatric and adult series compromise the survival benefit.
Patients who experience relapse or progressive HL post-alloSCT fare dismally. A
pooled analysis from 5 international transplant centers of 756 patients who
experienced relapsed HL after autologous stem cell transplant (ASCT) revealed a
median survival of 2.4 years, with fewer than 10% of patients alive at 5 years.
When the collected data were analyzed by decade in which treatment was
received, no difference in treatment outcome was apparent, suggesting that
introduction of novel treatment approaches and allogeneic transplantation has
not meaningfully improved OS (overall survival). Current therapies for
pediatric HL have changed dramatically to reduce these toxicities - high-dose
radiation therapy is no longer utilized, chemotherapy regimens utilize lower
doses of alkylating agents, hybrid regimens allow for lower doses of
anthracycline and bleomycin - minimizing the current late effects in patients
receiving modern therapy. However, there is still a need to investigate the
efficacy and safety of these regimens versus chemotherapy alone in children and
adolescents. Because late effects may take 10 to 30 years or more to become
clinically apparent, it is too early to conclude on the long-term safety of
these
treatments. The proposed pediatric study has been designed to study brentuximab
vedotin in patients with relapsed or refractory HL, where adult data in this
disease setting are presently available and where an unmet medical need for new
treatments currently exists.
Study objective
Primary
• To assess the safety profile and determine the pediatric maximum tolerated
dose and/or recommended phase 2 dose of brentuximab vedotin
• To assess the pharmacokinetics of brentuximab vedotin
• To determine the overall response rate (complete remission, partial
remission) with brentuximab vedotin.
Secundary
• To determine the overall response rate (complete remission, partial
remission) with brentuximab vedotin.
• To determine the time to progression, time to response, duration of response,
and eventfree, progression-free, and overall survival with brentuximab vedotin.
Explorative
• To assess immume reconstitution
Study design
This is a phase I/II, open-label, single-agent, multicenter, dose escalation
study of brentuximab vedotin in children with relapsed or refractory sALCL or
HL. Patients with primary mediastinal B cell lymphoma will be eligible during
phase I. The primary objectives of the study are to assess the safety and
pharmacokinetics, and determine the pediatric maximum tolerated dose (MTD)
and/or RP2D of brentuximab vedotin in children.
In addition, the immunogenicity and antitumor activity of brentuximab vedotin
will be evaluated in children. Overall response will be evaluated after 2
cycles of therapy. Objective response is to be assessed by an independent
review facility (IRF) according to the International Working Group (IWG)
Revised Response Criteria for Malignant Lymphoma.(1) Children who respond or
experience stable disease may receive up to 16 cycles of brentuximab vedotin.
Children who experience disease progression or have unacceptable toxicity at
any time will be withdrawn from treatment. All children will be followed for 12
months following the last dose of brentuximab vedotin to assess overall
survival. Brentuximab vedotin will be administered by intravenous (IV) infusion
once every 21 days in this study. Each 21-day treatment cycle is composed of 1
day of study drug treatment, followed by a monitoring period of 21 days. The
starting dose will be 1.4 mg/kg and escalation will proceed using a traditional
3 + 3 design to a maximum dose of 1.8 mg/kg.
Intervention
Patient can have up to 16 cycles of 21 days. On day one of each cycles patients
will get study medication. Dose is depending on the weight of the patient.
Study burden and risks
Please refer to section E8.
Landsdowne Street 40
Cambridge, MA 02139
US
Landsdowne Street 40
Cambridge, MA 02139
US
Listed location countries
Age
Inclusion criteria
1. Male or female patients aged 2 to < 18 years (5 to < 18 years for patients with HL).;2. Have a diagnosis of systemic anaplastic large-cell lymphoma, or Hodgkin lymphoma for which standard, curative, life-prolonging, or palliative treatment does not exist or is no longer effective. (Patients diagnosed with any relapsed or refractory CD30+ hematological malignancy [eg, primary mediastinal B-cell lymphoma] may be included in phase 1 of the study.);3. Patients with sALCL must have documented anaplastic lymphoma kinase (ALK) status.;4. Patients with HL must be in their second or later relapse, have failed systemic chemotherapy either as induction therapy for advanced stage disease or salvage therapy, and were ineligible for, refused, or previously received a stem cell transplant.;5. Patients with relapsed or refractory sALCL must be beyond first remission or refractory to front-line chemotherapy.;6. Performance score >= 60 from Lansky Play Performance Scale if <= 16 years;7. Female patients who are of childbearing potential, agree to practice 2 effective
methods of contraception, at the same time, from the time of signing the informed
consent form (ICF) through 6 months after the last dose of study drug, or agree to
completely abstain from heterosexual intercourse;8. Male patients, even if surgically sterile, who agree to practice effective barrier
contraception during the entire study treatment period and through 6 months after the
last dose of study drug, or agree to completely abstain from heterosexual intercourse;9. Voluntary written consent (and institution-specific assent as appropriate based upon
patient comprehension) must be given before performance of any study-related
procedure not part of standard medical care, with the understanding that
consent/assent may be withdrawn by the patient or patient guardian at any time
without prejudice to future medical care.;10. Suitable venous access for the study-required procedures.;11. Clinical laboratory values as specified below within 14 days before the first dose of
study drug:
• Absolute neutrophil count greater than or equal to 1,500/µL.
• Platelet count greater than or equal to 75,000/µL.
• Serum bilirubin level less than or equal to 1.5 * upper limits of normal (ULN).
• Serum creatinine less than or equal to 1.5 * ULN.
• Alanine aminotransferase (ALT or SGPT) and aspartate aminotransferase (AST
or SGOT) less than or equal to 2.5 * ULN.;12. Patients must have a radiographically or clinically evaluable tumor per the IWG(1)
criteria.
Exclusion criteria
1. Current diagnosis of primary cutaneous ALCL those with systemic ALCL are
eligible.
2. Received an allogeneic stem cell transplant < 6 months prior to first dose of study
medication, or presence of polymerase chain reaction (PCR)-detectable CMV in any
post-allogeneic transplant patient. (Prior PCR positivity that was successfully treated
is acceptable provided the baseline PCR result is negative prior to first dose of study
drug.)
3. Receiving immunosuppressive therapy.
4. Receiving systemic therapy for chronic graft-versus-host disease (topical therapy is
allowed).
5. Previous treatment with any anti-CD30 antibody.
6. Therapeutic monoclonal antibody use within the longer of 6 weeks or 5 plasma half lives.
7. Symptomatic cardiac disease including ventricular dysfunction, coronary artery
disease, or arrhythmias, if this would, in the opinion of the investigator or medical
monitor, interfere with assessment of efficacy or safety of the drug.
8. History of another primary malignancy not in remission for at least 3 years. (The
following are exempt from the 3-year limit: nonmelanoma skin cancer and cervical
carcinoma in situ on biopsy or a squamous intraepithelial lesion on Pap smear)
9. Known cerebral/meningeal disease, including signs or symptoms of
progressive multifocal leukoencephalopathy (PML).
10. History of cirrhosis.
11. Active systemic viral, bacterial, or fungal infection requiring antimicrobial, antiviral
therapy or antifungal therapy within 2 weeks prior to first dose of study drug (routine
antimicrobial prophylaxis is acceptable).
12. Concurrent therapy with other anti-neoplastic or experimental agents.
13. System corticosteroid therapy <14 days prior to first dose of study medication.
14. Any serious underlying medical condition that, in the opinion of the investigator or
medical monitor, would impair patient*s ability to receive or tolerate the planned
treatment.
15. Known hypersensitivity to recombinant proteins, murine proteins, or any excipient
contained in the drug formulation.
16. Received nitrogen mustard agents, melphalan, or BCNU therapy within 6 weeks
prior to first study dose.
17. Prior autologous hematopoietic stem cell infusion < 6 weeks prior to first study dose.
18. Grade 2 or greater unresolved toxicity from prior antineoplastic therapy.
19. Received a strong inhibitor of CYP3A4 < 2 weeks prior to first study dose.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2011-001240-29-NL |
| CCMO | NL38209.078.11 |