| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsed/Refractory Precursor B-cell or T-cell Acute Lymphoblastic Leukemia or Lymphoblastic Lymphoma |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10000845 |
| E.1.2 | Term | Acute lymphoblastic leukemia |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10066109 |
| E.1.2 | Term | Precursor B-lymphoblastic leukemia acute |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10066110 |
| E.1.2 | Term | T-cell lymphoblastic leukemia acute |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The main objective is to evaluate the efficacy of daratumumab in addition to standard chemotherapy in relapsed/refractory B-cell ALL and T-cell ALL as measured by the complete response (CR) rate. |
|
| E.2.2 | Secondary objectives of the trial |
- To assess the efficacy of daratumumab in addition to standard
chemotherapy, including ORR, relapse-free survival (RFS), EFS, and OS
in pediatric and young adult subjects with B-cell and T-cell ALL, 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 addition to
standard chemotherapy in pediatric and young adult subjects with B-cell
and T-cell ALL
- To assess the PK of daratumumab in pediatric and young adult subjects
with B-cell and T-cell ALL
- To assess daratumumab immunogenicity in pediatric and young adult
subjects with B-cell ALL and T-cell ALL
- To assess daratumumab concentration in cerebrospinal fluid (CSF) |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 m2 prior to enrollment (see Attachment 3).
6. Adequate liver function prior to enrollment 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 childbearing potential (defined as post-menarchal and sexually active until becoming post menopausal unless permanently sterile) 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 12 months after the last dose of any component of the treatment regimen. Permanent sterilization methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. 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. 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 12 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 |
|
| E.4 | Principal 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
2Active acute graft-versus-host disease of any grade or chronic graftversus- 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 enrollment or blinatumomab within 2 weeks prior to enrollment.
9.For subjects with T-cell ALL/LL only: prior cumulative anthracycline exposure must not exceed 400 mg/m^2 of doxorubicin or equivalent
10.Subject is:
●known to be seropositive for human immunodeficiency virus (HIV)
●seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg]).Subjects with resolved infection (ie,subjects who are HBsAg negative but positive for antibodies to hepatitis B core antigen [Anti-HBc] and/or antibodies to hepatitis B surface antigen [Anti-HBs]) must be screened using real-time polymerase chain reaction
(PCR) measurement of hepatitis B virus (HBV) DNA levels.Those who are PCR positive will be excluded. EXCEPTION: Subjects with serologic findings suggestive of HBV vaccination (Anti-HBs positivity as the only serologic marker) AND a known history of prior HBV vaccination, do not need to be tested for HBV DNA by PCR
●known to be seropositive for 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,methotrexate, vincristine, mAb (IRR is not considered hypersensitivity) or human proteins, or their excipients (refer to respective package inserts and Investigator's Brochure),or known sensitivity to mammalian-derived products.For subjects with Tcell ALL/LL only,known allergies to doxorubicin,cytarabine,cyclophosphamide,or 6-mercaptopurine.
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,breastfeeding,or planning to become pregnant while enrolled in this study or within 12 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. Subject is not affiliated to, or a beneficiary of, a social security category, per local regulatory requirements,if applicable
19. Subjects with infant leukemia (defined as under 1 year old at the time of initial diagnosis). These subjects will not be eligible for this study, even if they are greater than 1 year old at the time of relapse |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| 1. Complete response (CR) rate |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 1. Within 2 cycles of therapy for B-cell ALL and at the end of Cycle 1 for T-cell ALL |
|
| E.5.2 | Secondary end point(s) |
1. Overall response rate (ORR)
2. Event-free survival (EFS)
3. Relapse-free survival (RFS)
4. Overall survival (OS)
5. Minimal residual disease (MRD) negative rate
6. Proportion of subjects who receive an allogeneic Hematopoietic stem cell transplant (HSCT) after treatment with daratumumab
7. PK of daratumumab in pediatric and young adult subjects (Cmax and Cmin)
8. Daratumumab immunogenicity incidence in pediatric and young adult subjects with B-cell T-cell ALL/LL
9. Concentration of daratumumab in Cerebrospinal fluid (CSF) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1.End of bothCycle(1&2)for B&T-cell cohort andDay28 of every other cycle from C4untilCR for B-ALL/LL
2.Time from date of 1st treat.to 1st documented treat. failure,or date of relapse from CR,or death ,whichever occurs 1st
3.Time from CR to relapse fromCR or death due to any cause,whichever occurs 1st
4.Time from date of 1st treatment to date of death due to any cause
5.End of both Cycle(1&2)for T-cell coh. and Day28 of every other cycle from C4untilCR forB-ALL/LL
6.End of C1,2
7.B-cell cohort-Predose & at endof infusion on D1ofC1,2,3,6,9,EoT,follow-up Tcell cohort-Predose & atend of infusion at
C1D1,C2D1,22,EoT,follow-up
8.Bcohort-Predose on D1ofC1,2,6,9, EoT,follow-up T cohort-Predose on
D1ofC1,2, EoT,fu.
9.Bcohort-Predose on D1ofC1,2,3,4,6,9 T cohort-Predose on
C1D1,15,C2D2,15 |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Immunogenicity and Biomarker analyses |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 28 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Israel |
| United States |
| Belgium |
| France |
| Germany |
| Italy |
| Netherlands |
| Spain |
| Sweden |
| United Kingdom |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The study will end 1 year after the last subject has initiated treatment. A futility analysis will be performed after Stage 1 of the study and could result in the trial ending prior to this if specific, protocol-defined efficacy events are not met. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 14 |
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