Use of a New Medicine "Daratumumab" to Treat Left-over Cancer in a Blood Cancer Called "T Acute Lymphoblastic Leukemia"

Official title

Daratumumab for Minimal Residual Disease Eradication in T-Acute Lymphoblastic Leukemia - A Phase 2 Study

Overview

T-ALL (T-acute lymphoblastic leukemia) is an aggressive blood cancer, wherein patients who are MRD positive after two courses of induction chemotherapy have poor outcomes. This goal of this study is to determine if Daratumumab can make such T-ALL patients MRD negative. The main questions this study aims to answer are - 1. Whether MRD Positive T-ALL patients can become MRD negative after two doses of daratumumab? 2. Whether MRD Positive T-ALL patients can become MRD negative after four doses of daratumumab? 3. Whether addition of daratumumab can affect the risk of progression or death at 1-year? 4. Whether daratumumab is safe to use? Newly diagnosed patients of T-ALL who are MRD positive after two courses of induction chemotherapy will be eligible to receive daratumumab. These patients will receive two doses of weekly intravenous daratumumab at standard dose (16mg/kg), and will undergo repeat evaluation of MRD from bone marrow one week after the second dose of daratumumab. Patients who become MRD negative will continue chemotherapy as per institutional policy. Those who remain MRD positive will be eligible to receive two additional doses, and will undergo another bone marrow MRD testing one week after the fourth dose. Irrespective of the results after the fourth dose, patients will be continued on chemotherapy as per institutional policy.

Detailed description

Hypothesis - Daratumumab will increase the MRD negative CR rate in newly diagnosed T-ALL who are MRD positive after two-cycles of induction chemotherapy.

Rationale of dosing Daratumumab being a monoclonal antibody primarily depends on its target mediated clearance. In myeloma, dose finding studies of daratumumab showed that the drug at a dose of 16mg per kg was able to saturate all the receptors due to which a lower clearance and higher trough concentrations were observed. On the other hand, a lower dose of 8 mg/kg demonstrated higher clearance due to lack of complete target engagement / saturation. Hence, 16 mg/kg was the approved dose. In accordance with the above concept, daratumumab has been used in multiple indications apart from myeloma viz. PRCA post-transplant, Extranodal NK/T lymphoma, Blastic Plasmacytoid Dendritic Cell Neoplasm, at the myeloma approved dose of 16 mg/kg. Moreover, from its phenomenon of indirect coombs test positivity, it is evident that daratumumab binds CD38 antigen on RBCs, even though the expression of CD38 on RBCs is low. Its ability to bind to CD38 antigen across cell lineages, further supports that the same dose will be valid for T-ALL.

Method - T-ALL adult patients (on modified BFM-90 induction chemotherapy or any other pediatric inspired protocol) who are MRD positive by flow cytometry (≥0.01%) at end of phase 1a induction, will undergo a bone marrow-minimal residual disease (BM-MRD) testing at the end of phase 1b induction (or after 2 phases of induction of any pediatric inspired protocol), at count recovery (ANC\>1000/cumm, Platelet \>75,000/cumm).

Multicolor flow-cytometry for MRD will be performed using a 13-color T-MRD panel in Dx FLEX flow-cytometer (Beckman Coulter). The analysis will be performed with Kaluza version 2.0 software.

T-ALL patients in CR-1 who are MRD positive i.e., ≥0.01% on flow-cytometry at the end of phase 1b induction (two phases of chemotherapy) and CD38 positive (expression on \>=20% blasts) will be eligible for the study

Study schema MRD positive patients of T-ALL who fulfil criteria as mentioned above will be enrolled in the study. Before starting daratumumab, investigations will be performed as mentioned below. First dose of daratumumab will be administered as an in-patient for 24 hours, as per protocol mentioned below. Those who tolerate daratumumab well i.e., not more than grade 1 infusion related reaction (IRR) will be given subsequent doses on out-patient basis in day-care. BM aspirate for MRD analysis will be done 7days (± 2days) after second dose of daratumumab. Those who become MRD negative (\<0.01% by flow-cytometry), will be off-study and continued on conventional treatment regimen as per institution policy. Those who are still MRD positive (≥0.01% by flow-cytometry) after two doses, will be given two additional weekly doses of daratumumab. In patients who receive two additional doses, BM aspirate for MRD analysis will be done 7days (± 2days) after fourth dose of daratumumab. Irrespective of MRD result after fourth dose, patients will be continued on conventional treatment regimen as per institution policy. Last follow-up time point for SAE related to intervention will be four weeks after last dose of daratumumab.

Interventions

• Drug Daratumumab Injection
  Patients will receive intravenous daratumumab (16mg/kg per dose) once weekly for 2 doses. After 2 doses, they will undergo bone marrow examination for flow-cytometric MRD. Those who become MRD negative (less than 0.01% by flow-cytometry), will be off-study and continued on conventional treatment regimen as per institution policy. Hence, total duration in those who become MRD negative will be 3 weeks. However, those who are still MRD positive (more than or equal to 0.01% by flowcytometry) after

Primary outcome measures

• MRD negativity [Time frame: "week 3 after Daratumumab initiation"]

Secondary outcome measures (3)

• To determine cumulative incidence of MRD negativity [Time frame: "Upto week 5 after Daratumumab initiation"]
• Progression free survival [Time frame: "1-year after initiation of daratumumab"]
• Adverse events [Time frame: "From day of initiation of daratumumab till four weeks after the last dose of daratumumab"]

Eligibility criteria

Inclusion criteria

• Adults ≥18 - ≤65 years of age
• Baseline diagnosis of T-ALL, including ETP-ALL
• MRD positive (≥0.01%) disease (by flow-cytometry) assessed on BM after two phases of induction chemotherapy in CR-1
• CD38 positive
• Eastern cooperative oncology group (ECOG) performance status ≤2
• Acceptable liver functions, as specified below:

Total bilirubin <2 times upper limit of normal (ULN); Aspartate transaminase (AST;SGOT), alanine transaminase (ALT;SGPT) <3 ULN

• Subject ready to sign an informed consent form
• Patients with baseline CSF cytology positive, but who have cleared CSF by either modality (cytology or flow cytometry)

Exclusion criteria

• T-LBL (T-lymphoblastic lymphoma) without BM involvement
• Patients with persistently positive CSF cytology after two phases of induction or baseline testicular involvement
• Patients with symptomatic obstructive airway disease, as per assessing clinician
• Presence of an active systemic infection, as per assessing clinician
• New York Heart Association (NYHA) Class III or IV cardiac disease, or left ventricular ejection fraction <40%
• Human immunodeficiency virus (HIV) positive.
• Pregnant or breastfeeding female
• HBsAg positive or HBV-DNA positivity

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

India · 1 center

• Dr.Sumeet Mirgh — Navi Mumbai

Publications

• Usmani SZ, Weiss BM, Plesner T, Bahlis NJ, Belch A, Lonial S, Lokhorst HM, Voorhees PM, Richardson PG, Chari A, Sasser AK, Axel A, Feng H, Uhlar CM, Wang J, Khan I, Ahmadi T, Nahi H. Clinical efficacy of daratumumab monotherapy in patients with heavily pretreated relapsed or refractory multiple myeloma. Blood. 2016 Jul 7;128(1):37-44. doi: 10.1182/blood-2016-03-705210. Epub 2016 May 23. PMID 27216216
• Lokhorst HM, Plesner T, Laubach JP, Nahi H, Gimsing P, Hansson M, Minnema MC, Lassen U, Krejcik J, Palumbo A, van de Donk NW, Ahmadi T, Khan I, Uhlar CM, Wang J, Sasser AK, Losic N, Lisby S, Basse L, Brun N, Richardson PG. Targeting CD38 with Daratumumab Monotherapy in Multiple Myeloma. N Engl J Med. 2015 Sep 24;373(13):1207-19. doi: 10.1056/NEJMoa1506348. Epub 2015 Aug 26. PMID 26308596
• Lancman G, Arinsburg S, Jhang J, Cho HJ, Jagannath S, Madduri D, Parekh S, Richter J, Chari A. Blood Transfusion Management for Patients Treated With Anti-CD38 Monoclonal Antibodies. Front Immunol. 2018 Nov 15;9:2616. doi: 10.3389/fimmu.2018.02616. eCollection 2018. PMID 30498492
• Blair HA. Daratumumab: A Review in Relapsed and/or Refractory Multiple Myeloma. Drugs. 2017 Dec;77(18):2013-2024. doi: 10.1007/s40265-017-0837-7. PMID 29127588
• Michaleas S, Penninga E, Hovgaard D, Dalseg AM, Rosso A, Sarac SB, Jimenez JC, Fernandez LL, Fernandez CP, Mangas-SanJuan V, Garcia I, Payares-Herrera C, Sancho-Lopez A, Enzmann H, de Castro Lopes Silva MSS, Duarte S, Pignatti F. EMA Review of Daratumumab (Darzalex) for the Treatment of Adult Patients Newly Diagnosed with Multiple Myeloma. Oncologist. 2020 Dec;25(12):1067-1074. doi: 10.1002/onco.1 PMID 33026700
• Mirgh S, Sharma A, Folbs B, Khushoo V, Kapoor J, Tejwani N, Ahmed R, Agrawal N, Choudhary PS, Mehta P, Bhurani D. Daratumumab-based therapy after prior Azacytidine-Venetoclax in an octagenerian female with BPDCN (blastic plasmacytoid dendritic cell neoplasm) - a new perspective. Leuk Lymphoma. 2021 Dec;62(12):3039-3042. doi: 10.1080/10428194.2021.1941938. Epub 2021 Jun 21. No abstract available. PMID 34151693
• Huang H, Zhu J, Yao M, Kim TM, Yoon DH, Cho SG, Eom HS, Lim ST, Yeh SP, Song Y, Kwong YL, Kim JS, Jin J, Shi Y, Kim H, Qing M, Zhou T, Gao G, Dong Z, Qi M, Kim WS. Daratumumab monotherapy for patients with relapsed or refractory natural killer/T-cell lymphoma, nasal type: an open-label, single-arm, multicenter, phase 2 study. J Hematol Oncol. 2021 Feb 15;14(1):25. doi: 10.1186/s13045-020-01020-y. PMID 33588922
• Jeyaraman P, Borah P, Rajput P, Dayal N, Pathak S, Naithani R. Daratumumab for pure red cell aplasia post ABO incompatible allogeneic hematopoietic stem cell transplant for aplastic anemia. Blood Cells Mol Dis. 2021 May;88:102464. doi: 10.1016/j.bcmd.2020.102464. Epub 2020 Jul 2. PMID 32653327

Identifiers

NCT: NCT07021677 · 900938

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗