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Testing the Addition of Daratumumab to Chemotherapy for Treating Patients With Newly-Diagnosed T-Cell Lymphoblastic Leukemia (T-ALL) and T-Cell Lymphoblastic Lymphoma (T-LL)

ConditionsStage II T Lymphoblastic Leukemia/LymphomaStage III T Lymphoblastic Leukemia/LymphomaStage IV T Lymphoblastic Leukemia/LymphomaT Acute Lymphoblastic LeukemiaT Lymphoblastic Lymphoma
Trial statusNot yet recruiting
Trial phasePhase 2, Phase 3
Trial typeInterventional
Biological sexAll
Age365-21
SponsorChildren's Oncology Group

About this trial

This phase II/III trial tests the addition of daratumumab to chemotherapy for treating patients with newly-diagnosed T-ALL and T-LL. Daratumumab is in a class of medications called monoclonal antibodies. It binds to a protein called CD38, which is found on some types of immune cells and cancer cells. Daratumumab may block CD38 and help the immune system kill cancer cells. Chemotherapy drugs 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 chemotherapy with daratumumab may kill more cancer cells.

Eligibility criteria

This trial does not accept healthy volunteers

Qualifiers

All patients must be enrolled on APEC14B1 and consented to eligibility screening (part A) prior to treatment and enrolled on AALL2331.

Patients must be > 365 days and < 21 years of age at the time of diagnosis.

* Newly diagnosed T-cell acute lymphoblastic leukemia (T-ALL) or T-lineage lymphoblastic lymphoma (T-LL) stages II-IV.

Note: A diagnosis of T-ALL is established when leukemic blasts lack myeloperoxidase or evidence of B-lineage derivation (CD19/CD22/CD20), and express either surface or cytoplasmic CD3 or two or more of the antigens CD8, CD7, CD5, CD4, CD2 or CD1a, and are present either in peripheral blood or > 25% in the bone marrow. If surface CD3 is expressed on all leukemic cells, additional markers of immaturity, including TdT, CD34 or CD99 will be assessed for expression. Cases with uncertain expression will receive additional review within the appropriate Children's Oncology Group (COG) reference laboratory.

Disqualifiers

Diagnosis of Down syndrome (trisomy 21).

Patients with known Charcot-Marie-Tooth disease.

Steroid pretreatment: Prednisone or methylprednisolone for ≤ 120 hours (5 days) in the 7 days prior to initiating induction chemotherapy or for ≤ 336 hours (14 days) in the 28 days prior to initiation of protocol therapy does not affect eligibility.

Intrathecal cytarabine; or

Trial design

Design model

Parallel

Treatments tested in this trial

  • Biopsy Procedure

    Procedure/Surgery

    Undergo biopsy

  • Biospecimen Collection

    Procedure/Surgery

    Undergo blood sample collection

  • Bone Marrow Aspiration

    Procedure/Surgery

    Undergo bone marrow aspiration

  • Bone Marrow Biopsy

    Procedure/Surgery

    Undergo bone marrow biopsy

  • Bone Scan

    Procedure/Surgery

    Undergo bone scan

  • Bortezomib

    Drug

    Given IV or SC

  • Calaspargase Pegol

    Drug

    Given IV

  • Computed Tomography

    Procedure/Surgery

    Undergo CT

  • Cyclophosphamide

    Drug

    Given IV

  • Cytarabine

    Drug

    Given IT or IV or SC

  • Daratumumab

    Biological/Vaccine

    Given IV

  • Daunorubicin Hydrochloride

    Drug

    Given IV

  • Dexamethasone

    Drug

    Given PO or IV

  • Doxorubicin Hydrochloride

    Drug

    Given IV

  • Echocardiography Test

    Procedure/Surgery

    Undergo ECHO

  • Lumbar Puncture

    Procedure/Surgery

    Under lumbar puncture

  • Magnetic Resonance Imaging

    Procedure/Surgery

    Undergo MRI

  • Mercaptopurine Oral Suspension

    Drug

    Given PO

  • Methotrexate

    Drug

    Given IT or IV or PO

  • Methylprednisolone

    Drug

    Given IV

  • Nelarabine

    Drug

    Given IV

  • Pegaspargase

    Drug

    Given IV or IM

  • Positron Emission Tomography

    Procedure/Surgery

    Undergo PET or PET-CT

  • Prednisolone

    Drug

    Given PO or IV

  • Prednisone

    Drug

    Given PO or IV

  • Questionnaire Administration

    Other intervention

    Ancillary studies

  • Radiation Therapy

    Radiation

    Undergo radiation therapy

  • Therapeutic Hydrocortisone

    Drug

    Given IT

  • Thioguanine

    Drug

    Given PO

  • Ultrasound Imaging

    Procedure/Surgery

    Undergo ultrasound

  • Vincristine Sulfate

    Drug

    Given IV

Treatment groups

1,708 Participants
are divided into 4 treatment groups
Group A: Group I, Arm A (T-ALL, no daratumumab)Active comparator 26 interventions
Group B: Group I, Arm B (T-ALL, daratumumab)Experimental treatment 27 interventions
Group C: Group II, Arm C (T-LL, no daratumumab)Active comparator 29 interventions
Group D: Group II, Arm D (T-LL, daratumumab)Experimental treatment 30 interventions

Trial outcomes

Primary outcomes

1

Event-free survival (EFS) in patients with newly diagnosed T-cell lymphoblastic leukemia (T-ALL)

Will compare EFS in patients with newly diagnosed T-ALL who are randomized to either receive a modified augmented Berlin-Frankfurt-Munich (aBFM) chemotherapy backbone or a modified aBFM backbone with the addition of daratumumab. Patients without an EFS event will be censored at the date of last follow-up. The survival time analyses assume a Weibull distribution with a shape parameter of 0.45 (based on historical controls). A phase 2/3 design will be used.

Time frame
From date of randomization (randomization conducted at the end of induction [EOI]) to date of first event (consolidation failure, interim maintenance failure, relapse, secondary malignant neoplasm [SMN], death from any cause), assessed up to 4 years
2

EFS in patients with newly diagnosed T-cell lymphoblastic lymphoma (T-LL)

Will compare EFS in patients with newly diagnosed T-LL who are randomized to a modified aBFM chemotherapy backbone with bortezomib or to a modified aBFM backbone with bortezomib and the addition of daratumumab. Patients without an EFS event will be censored at the date of last follow-up. The survival time analyses assume a Weibull distribution with a shape parameter of 0.45 (based on historical controls).

Time frame
From date of randomization (randomization conducted at the EOI) to date of first event (consolidation failure, relapse, progressive disease, SMN, death from any cause), assessed up to 4 years

Secondary outcomes

1

Health-related quality of life (HRQoL)

Will compare HRQoL between patients with T-ALL or T-LL randomized to a modified aBFM backbone or to a modified aBFM backbone with the addition of daratumumab. Will use the Patient-Reported Outcomes Measurement Information System (PROMIS) Pediatric Global Health scale (PGH-7). The PROMIS PGH-7 has a standard deviation of 10 points, with higher scores indicating better HRQoL.

Time frame
Baseline (at time of randomization) to day 64 of consolidation
2

Incidence of therapy-related toxicity and tolerability

Will compare therapy-related toxicity and tolerability between patients with T-ALL or T-LL randomized to a modified aBFM backbone or to a modified aBFM backbone with the addition of daratumumab. Will be assessed for all patients and the rates compared between the randomized arms (T-ALL: arm A versus (vs) arm B and T-LL: arm C vs arm D). Rates by arm will be reviewed by the study committee on a monthly basis and will also be provided in the biannual reports to the Children's Oncology Group Data and Safety Monitoring Committee for review. Any concerns regarding excessive rates of any toxicities will be discussed in the context of any required therapy modifications.

Time frame
Assessed up to 3 cycles post randomization (each cycle is approximately 2-3 months)
3

Overall survival (OS) in patients with newly diagnosed T-ALL

Will compare OS in patients with newly diagnosed T-ALL who are randomized to either receive a modified aBFM chemotherapy backbone or a modified aBFM backbone with the addition of daratumumab. Patients who are alive will be censored at date of last follow-up. Comparison of OS between the two randomized arms will be conducted at the time of the final analysis for the primary objective (EFS). Analyses will be based on stratified log-rank tests. In addition, descriptive OS rates post randomization will be estimated using the Kaplan-Meier method and standard errors and confidence intervals estimated by the method of Peto. In particular, 4-year OS rates in arm A and arm B will be estimated. Estimation of treatment effect will be done using intent-to-treat (ITT) analysis. Hazard ratio (HR) and the confidence interval will be estimated based on Cox regression models as appropriate.

Time frame
From date of randomization (randomization conducted at the EOI) to date of death (death due to any cause), assessed up to 4 years
4

Overall survival (OS) in patients with newly diagnosed T-LL

Will compare OS in patients with newly diagnosed T-LL who are randomized to a modified aBFM chemotherapy backbone with bortezomib or to a modified aBFM backbone with bortezomib and the addition of daratumumab. Patients who are alive will be censored at date of last follow-up. Comparison of OS between the two randomized arms will be conducted at the time of the final analysis for the primary objective (EFS). Analyses will be based on log-rank tests. In addition, descriptive OS rates post randomization will be estimated using the Kaplan-Meier method and standard errors and confidence intervals estimated by the method of Peto. In particular, 4-year OS rates in arm C and arm D will be estimated. Estimation of treatment effect will be done using ITT analysis. HR and the confidence interval will be estimated based on Cox regression models as appropriate.

Time frame
From date of randomization (randomization conducted at the EOI) to date of death (death due to any cause), assessed up to 4 years

Other outcomes

1

EFS from end of induction patients with newly diagnosed T-LL

Will determine if minumal residual disease (MRD) testing in patients with newly diagnosed T-LL at EOI can predict EFS. EFS will be compared for T-LL patients with negative MRD (defined as \< 0.1%) and those who with MRD ≥ 0.1% at the EOI. EFS will be defined as time from the EOI to date of first event (consolidation failure, relapse, progressive disease, SMN, death from any cause), and patients without an EFS event will be censored at the date of last follow-up. In addition, comparison of EFS by the EOI MRD status (positive vs negative) will be conducted among randomized patients. Comparisons will be conducted by treatment arms. A potential interaction between MRD at the EOI with treatment arms will be assessed.

Time frame
Assessed up to 4 years
2

OS from end of Induction in patients with newly diagnosed T-LL

Will determine if MRD testing in patients with newly diagnosed T-LL at EOI can predict OS. OS will be compared for T-LL patients with negative MRD (defined as \< 0.1%) and those who with MRD ≥ 0.1% at the EOI. OS will be defined as time from the EOI to date of death, with patients who are alive being censored at date of last follow-up. In addition, comparison of OS by the EOI MRD status (positive vs negative) will be conducted among randomized patients. Comparisons will be conducted by treatment arms. A potential interaction between MRD at the EOI with treatment arms will be assessed.

Time frame
Assessed up to 4 years
3

Immunophenotype in T-ALL patients

Will describe changes in T-ALL patients in the immunophenotype (specifically CD38 surface expression on T-ALL/T-LL blasts) correlate changes with clinical outcomes and demographic variables. Differences between patients treated with daratumumab and those who are not treated with daratumumab will be assessed; the comparisons between arm A and arm B will be based on test of proportions, Fisher's exact test or logistic regression, as appropriate.

Time frame
Assessed at baseline, end of Induction (Induction is 29 days), and relapse (up to 10 years)
4

Development of anti-daratumumab antibodies in T-ALL patients

Will describe the development of anti-daratumumab antibodies over the course of treatment and correlate changes with clinical outcomes and demographic variables. Analyses will be restricted to T-ALL patients randomized to arm B. Analyses will be based on test of proportions, Fisher exact test, logistic regression, log-rank test, semi-parametric or parametric survival analysis, as appropriate.

Time frame
Assessed up to 3 years

Locations

This trial has no locations.

Sponsors and contacts

Click on the lead sponsor to view all of their trials.

Children's Oncology Group

Lead sponsor

Source ClinicalTrials.gov

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