The primary objective is to evaluate the efficacy of daratumumab in addition to standard chemotherapy in relapsed/refractory B-cell acute lymphoblastic leukemia (ALL) and T-cell ALL as measured by the complete response (CR) rate.The secondary…
ID
Source
Brief title
Condition
- Other condition
- Leukaemias
Synonym
Health condition
Voorloper B en T-cel Acute lymfatische leukemie en Lymfoblastair lymfoom,
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary Endpoint
The primary endpoint is CR rate within 2 cycles of therapy for B-cell ALL and
at the end of Cycle 1 for T-cell ALL. CR is defined as:
* Less than 5% blasts in the bone marrow
* No evidence of circulating blasts or extramedullary disease
* Full recovery of peripheral blood counts:
o Platelets >100x109/L
o Absolute neutrophil count (ANC) >1.0x109/L
Secondary outcome
Secondary Endpoints
The secondary endpoints include:
* ORR, defined as CR or CRi for ALL
o CR is defined as above
o CRi is defined as:
* Less than 5% blasts in the bone marrow
* No evidence of circulating blasts or extramedullary disease
* Partial recovery of peripheral blood counts not meeting criteria for CR noted
above
* EFS, defined as the time from the date of first treatment to the first
documented treatment failure (ie, disease progression) or date of relapse from
CR or death due to any cause, whichever occurs first
* RFS, defined as the time from CR to relapse from CR or death due to any
cause, whichever occurs first
* OS, defined as the time from the date of first treatment to the date of death
due to any cause
* MRD negative rate, defined as the proportion of subjects who are MRD negative
* Proportion of subjects who receive an allogeneic HSCT after treatment with
daratumumab
* PK of daratumumab in pediatric and young adult subjects (Cmax and Cmin)
* Daratumumab immunogenicity incidence in pediatric and young adult subjects
with B-cell T-cell ALL/LL
* Concentration of daratumumab in CSF
Exploratory Endpoints
The exploratory endpoints include:
* Biomarkers predictive of response or resistance to therapy
* Expression of CD38 at study entry and at relapse
Background summary
Acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LL) comprise a
heterogeneous group of lymphoid disorders that result from a monoclonal
proliferation and expansion of immature lymphoid cells in the bone marrow,
blood, and other organs. Immunophenotypic analysis permits sub-classification
into B-cell and T-cell lineage types. As a result of leukemic blast
infiltration of the bone marrow, patients present with signs of bone
marrow failure, including anemia, thrombocytopenia, and neutropenia. Clinical
manifestations include fatigue, bleeding, and fever. Clinical signs include
pallor, petechiae, weight loss, lymphadenopathy, and hepatosplenomegaly. Other
symptoms of ALL and LL include bone pain and dyspnea. Central nervous system
(CNS) involvement may include leptomeningeal disease or an intracranial or
spinal mass.Testicular involvement occurs in less than 3% of boys, who may
present with painless testicular enlargement, which is most often unilateral on
initial presentation.Patients with mediastinal masses, which commonly occur in
T-cell ALL and LL, may present with dyspnea, wheezing, or shortness of breath
and possibly with superior vena cava syndrome.
ALL is the most common pediatric malignancy, accounting for up to 30% of newly
diagnosed cases of cancer in children. The estimated annual incidence of ALL is
6,500 in the United States (US) and 5,000 in the European Union (EU). B-cell
ALL accounts for 80 to 85% of cases of ALL and T-cell ALL accounts for
approximately 10 to 15% cases of ALL. LL is considered a form of non-Hodgkin
lymphoma (NHL). It accounts for 20% of NHL in children. T-cell LL accounts for
75% of the cases of LL and B-cell LL accounts for 25% of cases. The World
Health Organization classifies LL as the same disease as ALL. As such, both
diseases commonly are studied in the same treatment protocols.
While pediatric ALL and LL remain highly curable, 20 to 25% of patients will be
refractory to or relapse after frontline treatment. In B-cell ALL, relapse is
risk-stratified and treatment is assigned accordingly based on timing of
relapse from initial diagnosis and the site of relapse (extramedullary vs.
medullary or combined). For B-cell ALL, depending on the site of relapse and
the timing of relapse, 5-year overall survival (OS) ranges from 25% for the
very early medullary/combined relapsed patients to 60%-70% for patients with
isolated extramedullary
relapse. Relapsed T-cell ALL is associated with an even worse prognosis with
only 7 to 23% of patients surviving for 3 to 5 years. Patients with B-cell LL
and T-cell LL have particularly dismal long-term outcomes due to difficulty of
achieving second remission, with reported 5-year OS 14% and 8-year OS of 9%.
The best chance for achieving long-term survival for T-cell ALL and LL is to
induce a second complete remission followed by hematopoietic stem cell
transplant (HSCT).
First re-induction consists of multi-drug chemotherapy with the goal to achieve
CR. Additionally, CNS directed therapy is provided via intrathecal chemotherapy
with methotrexate alone or methotrexate with cytarabine and hydrocortisone
(triple intrathecal chemotherapy) to clear CNS leukemia or to prophylax against
spread of disease to the CNS. For many patients who achieve CR, this is
followed by an allogeneic HSCT.
One re-induction regimen (prednisone, vincristine, doxorubicin, and
PEG-asparaginase) was evaluated in a single-arm Phase 2 study of patients with
relapsed B-cell and T-cell ALL in first relapse. The rate of CR was 68% for
patients with B-cell ALL with early relapse (n=63) and 17% for patients with
T-cell ALL with early relapse (n=6). The 4-month event-free survival (EFS) was
62% and the 12-month EFS was only 35% for all early relapses (<36 months); no
subjects with relapsed T-cell ALL survived longer than 10 months. The most
common Grade 3 or higher adverse events in 124 subjects overall other than
hematologic toxicity (neutropenia 97.6%, thrombocytopenia 79.8%, and anemia
62.9%) were febrile neutropenia (40.3%),hypofibrinogenemia (32.3%), and
infection with Grade 3/4 neutropenia (19.4%). Given the high CR rate and
tolerable safety profile of this regimen, this has become the standard backbone
for the Children*s Oncology Group (COG) with which to evaluate the addition of
novel therapies. As such, bortezomib is being combined with this standard
backbone of prednisone, vincristine, doxorubicin, and PEG-asparaginase, in an
ongoing Phase 2 COG study AALL07P1 for patients
with B-cell ALL in early relapse or T-cell ALL/LL in first relapse.
Several new approaches to treating patients with relapsed B-cell ALL/LL have
been developed in the last 5 years, including agents that target CD19, such as
the bispecific antibody blinatumomab. The CR rate after single-agent
blinatumomab treatment for relapsed/refractory B-ALL was 39%. This agent is now
being evaluated in combination with chemotherapy for the treatment of patients
with relapsed B-cell ALL. However, neurological toxicity is a concern with this
agent and can lead to treatment interruptions or discontinuations
Another strategy being actively investigated in ALL is chimeric antigen
receptor (CAR) T-cell immunotherapy. Among 30 subjects (25 pediatric, 5 adult)
with relapsed or refractory ALL treated with CTL019, there was a CR rate of 90%
at 1 month post-infusion. At 6 months, the EFS rate was 67% and the OS rate was
78%. Cytokine-release syndrome was seen in all subjects (mild to moderate in 22
subjects and severe [requiring intensive care with respiratory support] in 8
subjects), while neurologic toxic effects were seen in 13 subjects. Long-term
outcomes remain unclear with this novel therapy.
Inotuzumab ozogamicin, an antibody-drug conjugate targeting CD22, has been
evaluated in adults; however, while initial response rates are high (CR of
80.7%) in the Phase 3 pivotal trial, the duration remains short with a median
OS of only 5 months. Liver-related toxicity is common with 11% of subjects
experiencing veno-occlusive disease. This agent is now being evaluated in
children.
The most recent drug approved for T-cell ALL/LL is nelarabine, which was
approved in 2005. In a phase 2 study, nelarabine treatment resulted in an
overall response rate (ORR) of 55% (n=34) and CR rate of 47% for patients with
T-cell ALL in first relapse/refractory disease and an ORR of 43% with a CR rate
of 14% in patients with relapsed T-cell LL (n=7).Nelarabine has significant
neurologic toxicity that can be irreversible. Combining nelarabine with
cyclophosphamide and etoposide as a reinduction regimen for relapsed T-cell
ALL/LL resulted in a 44% CR rate in subjects with T-cell ALL/LL in first
relapse.While novel treatment modalities including BiTEs (blinatumomab),
monoclonal antibodies (mAbs) (inotuzumab), CAR T-cell immunotherapy, and the
deoxyguanosine analogue nelarabine have shown improved rates of complete
remission in relapsed/refractory ALL/LL, these gains
have not translated to improvements in median OS and duration of response
remains limited. Additionally, these novel agents have significant side effects
that influence their tolerability. New agents are needed with improved safety
profiles and the ability to improve duration of response and long-term survival
in relapsed/refractory B-cell and T-cell ALL/LL.
The primary hypothesis for each ALL subtype is as follows:
• For relapsed/refractory precursor B-cell ALL, treatment with daratumumab in
combination with vincristine and prednisone will result in a CR rate of 40% or
higher.
• For relapsed/refractor T-cell ALL, treatment with daratumumab in combination
with doxorubicin, prednisone, vincristine, and asparaginase will result in a CR
rate of 60% or higher
Study objective
The primary objective is to evaluate the efficacy of daratumumab in addition to
standard chemotherapy in relapsed/refractory B-cell acute lymphoblastic
leukemia (ALL) and T-cell ALL as measured by the complete response (CR) rate.
The secondary objectives include the following:
* To assess the efficacy of daratumumab, including overall response rate (ORR),
relapse-free
survival (RFS), event-free survival (EFS), and overall survival (OS) in
pediatric and young adult
subjects with B-cell and T-cell ALL/lymphoblastic lymphoma (LL), and minimal
residual disease
(MRD) negative rate in subjects with B-cell and T-cell ALL
* To assess the safety and tolerability of daratumumab in pediatric and young
adult subjects with
B-cell and T-cell ALL/LL
* To assess the pharmacokinetics (PK) of daratumumab in pediatric and young
adult subjects with
B-cell and T-cell ALL/LL
* To assess daratumumab immunogenicity in pediatric and young adult subjects
with B-cell ALL
and T-cell ALL/LL
* To assess daratumumab concentration in cerebrospinal fluid (CSF)
The exploratory objectives include the following:
* To explore biomarkers predictive of response or resistance to therapy
* To assess expression of CD38 at study entry and at relapse
Study design
This is a Phase 2, open-label, multicenter study to evaluate the efficacy,
safety, and PK of daratumumab in approximately 49 subjects aged >=1 to <18 with
relapsed/refractory ALL and a maximum of 69 total subjects >=1 and <=30 years of
age with relapsed or refractory ALL/LL. Cohort 1 will evaluate
daratumumab in combination with vincristine and prednisone in subjects with
B-cell ALL/LL in second relapse or greater. Cohort 2 will evaluate daratumumab
in combination with a standard 4-drug re-induction regimen in subjects with
T-cell ALL/LL in first relapse. There will be an initial safety run-in period
for evaluation of dose-limiting toxicities. A Safety Evaluation Team will be
commissioned for this study. The sponsor plans to enroll a minimum of 3
subjects with ALL in each of the following age groups in both cohorts: 1 to 6,
7 to 12, and 13 to <18 years if that cohort proceeds to stage 2 of the study.
Intervention
Subjects with B-cell ALL/LL will receive treatment continuously in 28-day
cycles until disease progression or unacceptable toxicity. Treatment will
consist of daratumumab 16 mg/kg IV weekly for 8 doses, then every 2 weeks for 8
doses, then every 28 days thereafter; vincristine 1.5 mg/m2 (maximum 2 mg) IV
weekly for 4 doses, then every 2 weeks for 2 doses, then every 28 days
thereafter; and prednisone
40 mg/m2 orally daily for 28 days, then pulses on the first 5 days of each
cycle thereafter.
Subjects with T-cell ALL/LL will receive up to two 28-day cycles of therapy.
Subjects who achieve CR should proceed to allogeneic hematopoietic stem cell
transplant off study. Cycle 1 treatment consists of daratumumab 16 mg/kg IV
weekly for 4 doses, vincristine 1.5 mg/m2 (maximum 2 mg) IV weekly for 4 doses,
prednisone 40 mg/m2 orally daily for 28 days, doxorubicin 60 mg/m2 IV once, and
peg-asparaginase 2500 U/m2 IV twice. Cycle 2 treatment consists of daratumumab
16 mg/kg IV weekly for 4 doses, cyclophosphamide IV 1 g/m2 once, cytarabine 75
mg/m2 IV/subcutaneous for 8 doses, 6-mercaptopurine 60 mg/m2 orally daily for
14 doses, and methotrexate 5 g/m2 IV once. Subjects in both cohorts will also
receive age-adjusted treatment with intrathecal methotrexate (for subjects
without central nervous system [CNS] involvement) or intrathecal
methotrexate-hydrocortisonecytarabine (for subjects with CNS involvement).
Study burden and risks
For a detailed overview of all assessments done during the study, please see
the "Time and events schedule" in the protocol.
Graaf Engelbertlaan 75
Breda 4837 DS
NL
Graaf Engelbertlaan 75
Breda 4837 DS
NL
Listed location countries
Age
Inclusion criteria
Each potential subject must satisfy all the following criteria to be enrolled in the study:;1. >=1 and <=30 years of age;2. Documented ALL or LL as defined by the criteria below:;a) B-cell cohort:;Stage 1: ;- ALL in second or greater relapse or refractory to 2 prior induction;regimens with >=5% blasts in the bone marrow and aged 1 to <18 years;Stage 2:;- ALL in second or greater relapse or refractory to 2 prior induction;regimens with >=5% blasts in the bone marrow and aged 1 to 30 years;- LL in second or greater relapse or refractory to 2 prior induction;regimens and biopsy proven and with evidence of measurable disease;by radiologic criteria and aged 1 to 30 years;b) T-cell cohort:;Stage 1:;- ALL in first relapse or refractory to 1 prior induction/consolidation;regimen with >=5% blasts in the bone marrow and aged 1 to <18 years;Stage 2:;- ALL in first relapse or refractory to 1 prior induction/consolidation;regimen with >=5% blasts in the bone marrow and aged 1 to 30 years;- LL in first relapse or refractory to 1 prior induction/consolidation;regimen biopsy proven and with evidence of measurable disease by;radiologic criteria and aged 1 to 30 years;3. Performance status >=70 by Lansky scale (for subjects <16 years of age) or Karnofsky scale (for subjects >=16 years of age);4. Adequate hematology laboratory values at Cycle 1 Day 1 pre-dosing defined as follows:;a. Hemoglobin >=7.5 g/dL (>=5 mmol/L; prior red blood cell [RBC] transfusion is permitted);b. Platelet count >=10 × 109/L (prior platelet transfusion is permitted);5. Adequate renal function defined as normal serum creatinine for the subject*s age or creatinine clearance or radioisotope glomerular filtration rate (GFR) 70 mL/min/1.73 m^2 at Cycle 1 Day 1 pre-dosing;6. Adequate liver function at Cycle 1 Day 1 pre-dosing defined as:;a. Alanine aminotransferase level <=2.5x the upper limit of normal (ULN);b. Aspartate aminotransferase level <=2.5xULN, and;c. Total bilirubin <=2x ULN or direct bilirubin level <=2.0xULN;7. Female subjects of reproductive potential prior to initiation of the study or during the study (should reproductive potential change during the study) must commit either to abstain continuously from heterosexual sexual intercourse or to use 2 methods of reliable birth control simultaneously during the Treatment Period, during any dose interruptions, and for 6 months after the last dose of any component of the treatment regimen. 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. Birth control methods must include one highly effective method of contraception (tubal ligation, intrauterine device, hormonal [birth control pills, injections, hormonal patches, vaginal rings or implants], or partner*s vasectomy) and one additional effective contraceptive method (male latex or synthetic condom, diaphragm, or cervical cap). Contraception must begin 4 weeks prior to dosing. Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy;8. During the study and for 6 months after receiving the last dose of any component of the treatment regimen, female subjects must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction;9. Male subjects of reproductive potential who are sexually active with females of reproductive potential must always use a latex or synthetic condom during the study and for 6 months after discontinuing study treatment (even after a successful vasectomy);10. Male subjects of reproductive potential must not donate sperm during the study or for 6 months after the last dose of study treatment;11. The informed consent form (ICF) must be signed by a 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 according to country-specific or site-specific standards;12. Must be willing and able to adhere to the prohibitions and restrictions specified in this protocol
Exclusion criteria
Any potential subject who meets any of the following criteria will be excluded from participating in the study:;1. Received an allogeneic hematopoietic transplant within 3 months of screening;2 Active acute graft-versus-host disease of any grade or chronic graft-versus-host disease of Grade 2 or higher;3. Received immunosuppression post hematopoietic transplant within 1 month of study entry.;4. Philadelphia chromosome positive (Ph+) B-cell ALL eligible for tyrosine kinase inhibitor therapy;5. Has either of the following:;a. Evidence of dyspnea at rest or oxygen saturation <=94%.;b. Known moderate or severe persistent asthma within the past 2 years, or uncontrolled asthma of any classification. Note that subjects who currently have controlled intermittent asthma or controlled mild persistent asthma may participate in the study;6. Down syndrome, juvenile myelomonocytic leukemia, Fanconi anemia, Kostmann syndrome, Shwachman syndrome, or any other known bone marrow failure syndrome;7. Prior exposure to daratumumab or other anti-CD38 therapies;8. Prior cancer immunotherapy (ie, CAR-T, inotuzumab) within 4 weeks prior to start of daratumumab treatment or blinatumomab within 2 weeks prior to the start of daratumumab treatment;9. For subjects with T-cell ALL/LL only: prior cumulative anthracycline exposure must not exceed 400 mg/m^2 (each 10 mg/m^2 of idarubicin should be calculated as the equivalent of 30 mg/m^2 of doxorubicin);10. Subject is known to be seropositive for human immunodeficiency virus, hepatitis B (defined by a positive test for hepatitis B surface antigen or antibodies to hepatitis B surface and core antigens), or hepatitis C (except in the setting of a sustained virologic response (SVR), defined as aviremia at least 12 weeks after completion of antiviral therapy);11. Screening 12-lead electrocardiogram (ECG) showing a baseline QT interval >470 msec or Grade 3 or higher cardiac disorders (according to National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] version 4.03);12. Known allergies, hypersensitivity, or intolerance to mannitol, glucocorticoid, doxorubicin, cytarabine, methotrexate, vincristine, cyclophosphamide, 6-mercaptopurine, mAb (IRR is not considered hypersensitivity) or human proteins, or their excipients, or known sensitivity to mammalian-derived products;13. Received an investigational drug, was vaccinated with live attenuated vaccines, or used an invasive investigational medical device within 4 weeks before the planned first dose of study drug, or is currently being treated in an investigational study.;14. Pregnant, breast-feeding, or planning to become pregnant while enrolled in this study or within 6 months after the last dose of any component of the treatment regimen;15. Plans to father a child while enrolled in this study or within 6 months after the last dose of any component of the treatment regimen;16. Subject has any concurrent medical or psychiatric condition or disease (eg, active systemic infection, uncontrolled diabetes, acute diffuse infiltrative pulmonary disease) that is likely to interfere with the study procedures or results, or that in the opinion of the investigator, would constitute a hazard for participating in this study;17. Major surgery within 2 weeks before screening, or will not have fully recovered from surgery, or has surgery planned during the time the subject is expected to participate in the study or within 2 weeks after the last dose of study drug administration;Note: Subjects with planned surgical procedures to be conducted under local anesthesia may participate ;18. Subject is known or suspected of not being able to comply with the study protocol (eg, because of alcoholism, drug dependency, or psychological disorder). Subject has any condition for which, in the opinion of the investigator, participation would not be in the best interest of the subject (eg, compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments. Subject is taking any prohibited medications listed in Section 8 of protocol. ;NOTE: Investigators should ensure that all study enrollment criteria have been met at screening. If a subject's clinical status changes (including any available laboratory results or receipt of additional medical records) after screening but before the first dose of study drug is given such that he or she no longer meets all eligibility criteria, then the subject should be excluded from participation in the study.
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
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In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2017-003377-34-NL |
| ClinicalTrials.gov | NCT03384654 |
| CCMO | NL64350.078.18 |