Neoplasms

Blood and Lymph Conditions

All Conditions

Immune System Diseases

Rare Diseases

Leukemia

Precursor Cell Lymphoblastic Leukemia-Lymphoma

Leukemia, Lymphoid

Lymphoma

Neoplasms by Histologic Type

Hematologic Diseases

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Acute Lymphoblastic Leukemia

Lymphoblastic Lymphoma

Acute Graft Versus Host Disease

Lymphosarcoma

Anti-Infective Agents

Antineoplastic Agents

All Drugs and Chemicals

Antirheumatic Agents

Anti-Inflammatory Agents

Antiemetics

Gastrointestinal Agents

Dermatologic Agents

Reproductive Control Agents

Cytarabine

Cyclophosphamide

Doxorubicin

Liposomal doxorubicin

Dexamethasone

Methotrexate

Rituximab

Vincristine

Dexamethasone acetate

Mesna

Anti-Bacterial Agents

Antibiotics, Antitubercular

Enzyme Inhibitors

The patient receive 2 different drug combinations on this study. The first combination will consist of an intensive chemotherapy regimen (cyclophosphamide, mesna, methotrexate, doxorubicin liposomal or doxorubicin, vincristine, ARA-C (cytarabine) and dexamethasone). The second combination will consist of another intensive chemotherapy regimen (methotrexate and Ara-C \[cytarabine\]).

* Cyclophosphamide
* Mesna
* Methotrexate
* Doxorubicin liposomal
* Vincristine
* Dexamethasone
* Rituximab
* Cytarabine

doxorubicin liposomal

Giovanni Martinelli, MD

My-HyperCVAD in the Treatment of Relapsed Refractory Adult Acute Lymphoid Leukemia

Open Label, Non-randomized, Phase II Study on Fractioned Cyclophosphamide, Vincristine, Liposomal Doxorubicin or Doxorubicin, and Dexamethasone (MY HYPER-CVAD) in the Treatment of Relapsed Refractory Adult Acute Lymphoid Leukemia

University of Bologna

Giovanni Martinelli

Antibodies

Antibodies, Bispecific

Immunoglobulins

Blinatumomab

Participants received blinatumomab 15 μg/m²/day as a continuous intravenous infusion at a constant flow rate over 4 weeks followed by a 2-week treatment-free interval for up to 5 consecutive cycles.

Participants received blinatumomab by continuous intravenous infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 5 μg/m²/day for the first seven days of treatment, followed by 15 μg/m²/day starting from Week 2 of treatment.

Participants received blinatumomab by continuous intravenous infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 5 μg/m²/day for the first seven days of treatment, a dose of 15 μg/m²/day in the subsequent 7 days, followed by 30 μg/m²/day starting from Week 3 of treatment.

Continuous intravenous infusion over four weeks per treatment cycle

Max Topp, MD

The purpose of this study is to determine whether the bispecific T-cell engager blinatumomab is effective, safe and tolerable in the treatment of patients with relapsed/refractory B-precursor ALL.

Relapsed/refractory B-precursor ALL in adult patients is an aggressive malignant disease with dismal prognosis and unmet medical need. Additional therapeutic approaches are urgently needed. Blinatumomab is a bispecific single-chain antibody construct designed to link B cells and T cells resulting in T cell activation and a cytotoxic T cell response against CD19 expressing cells. The purpose of this study is to investigate the efficacy, safety and tolerability of different doses of the bispecific T-cell engager blinatumomab in adult patients with relapsed/refractory B-precursor ALL. Patrticipants will receive up to five 4-week cycles of intravenous blinatumomab treatment.

Study of the BiTE® Blinatumomab (MT103) in Adult Patients With Relapsed/Refractory B-Precursor Acute Lymphoblastic Leukemia (ALL)

An Open Label, Multicenter, Exploratory Phase II Study to Evaluate the Efficacy, Safety, and Tolerability of the BiTE® Antibody Blinatumomab in Adult Patients With Relapsed/Refractory B-precursor Acute Lymphoblastic Leukemia (ALL)

At the end of each infusion period, a bone marrow aspiration/biopsy was performed to evaluate the efficacy of blinatumomab. All hematological assessments of bone marrow were reviewed in a central reference laboratory. Hematological remissions were defined by the following criteria:

Complete Response/Remission (CR):

* Less than or equal to 5% blasts in the bone marrow
* No evidence of circulating blasts or extramedullar disease
* Full recovery of peripheral blood counts:

  * Platelets \> 100,000/μL
  * Hemoglobin ≥ 11 g/dL
  * Absolute neutrophil count (ANC) \> 1,500/μL

Complete Remission with only Partial Hematological Recovery (CRh\*):

* Less than or equal to 5% blasts in the bone marrow
* No evidence of circulating blasts or extramedullar disease
* Partial recovery of peripheral blood counts:

  * Platelets \> 50,000/μL
  * Hemoglobin ≥ 7 g/dL
  * ANC \> 500/μL.

At the end of each infusion period, a bone marrow aspiration/biopsy was performed to evaluate the efficacy of blinatumomab. All hematological assessments of bone marrow were reviewed in a central reference laboratory. Complete Response/Remission (CR) was defined by the following criteria:

* Less than or equal to 5% blasts in the bone marrow
* No evidence of circulating blasts or extramedullar disease
* Full recovery of peripheral blood counts:

  * Platelets \> 100,000/μL
  * Hemoglobin ≥ 11 g/dL
  * Absolute neutrophil count (ANC) \> 1,500/μL

At the end of each infusion period, a bone marrow aspiration/biopsy was performed to evaluate the efficacy of blinatumomab. All hematological assessments of bone marrow were reviewed in a central reference laboratory. Complete remission with only partial hematological recovery (CRh\*) was defined by the following criteria:

* Less than or equal to 5% blasts in the bone marrow
* No evidence of circulating blasts or extramedullar disease
* Partial recovery of peripheral blood counts:

  * Platelets \> 50,000/μL
  * Hemoglobin ≥ 7 g/dL
  * ANC \> 500/μL.

At the end of each infusion period, a bone marrow aspiration/biopsy was performed to evaluate the efficacy of blinatumomab. All hematological assessments of bone marrow were reviewed in a central reference laboratory. Partial remission was defined by the following criteria:

• Bone marrow blasts ≤ 25%

A minimal residual disease (MRD) response is defined as MRD \< 10\^-4 blasts/nucleated cells based on polymerase chain reaction (PCR) evaluation of individual rearrangements of immunoglobulin or T cell receptor genes.

The percentage of participants who underwent immediate allogeneic HSCT (defined as those in remission who undergo HSCT without receiving any other treatments) after having discontinued or completed the core study.

Time to hematological relapse was measured for participants who achieved a CR or CRh\* during the core study and was measured from the time the participant first achieved remission until first documented relapse or death due to disease progression. Participants without a documented relapse (hematological or extramedullary) and who did not die were censored at the time of their last bone marrow assessment or their last survival follow-up visit confirming remission. Participants who died without having reported hematological relapse or without showing any clinical sign of disease progression were censored on their day of death.

Hematological Relapse was defined as:

* Proportion of blasts in bone marrow \> 5%
* Extramedullary relapse.

Time to hematological relapse was analyzed by Kaplan-Meier methods.

Relapse-free survival was measured only for participants who achieved a CR or CRh\* during the core study and was measured from the time the participant first achieved remission until first documented relapse or death due to any cause. Participants without a documented relapse (hematological or extramedullary) or who did not die were censored at the time of their last bone marrow assessment or their last survival follow-up visit confirming remission. Relapse-free survival was estimated using Kaplan-Meier methods.

Overall survival was measured for all participants from the date of first infusion of blinatumomab until the date of death due to any cause. Participants who did not die were censored on the last documented visit date. Overall survival was estimated using Kaplan-Meier methods.

Adverse events were evaluated for severity according to the grading scale provided in the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 and according to the following:

Grade I (mild); Grade 2 (moderate); Grade 3 (severe - significantly limits the patient's ability to perform routine activities despite symptomatic therapy; Grade 4 (life-threatening); Grade 5 (death).

The investigator used medical judgment to determine if there was a causal relationship (ie, certain, probable, possible, unlikely, not related) between an adverse event and blinatumomab.

A serious adverse event is any untoward medical occurrence or effect, that at any dose:

resulted in death, was life-threatening, required or prolonged hospitalization, resulted in persistent or significant disability or incapacity, is a congenital anomaly or birth defect or is a medically important condition.

The steady state concentration of blinatumomab was summarized as the observed concentrations collected at least 10 hours after the intravenous infusion was started for cycle 1 and cycle 2, respectively. Actual doses administered were used in the analysis.

Concentrations below the limit of detection (3 pg/mL) were set to zero before data analysis and concentrations below the lower limit of quantitation (50 pg/mL) were excluded from analysis.

Clearance was calculated as R0/Css; where R0 is the infusion rate (μg/m\^2/hr) and Css is the steady state concentration.

The activation of immune effector cells was monitored by the measurement of peripheral blood cytokine levels including interleukin (IL)-2, IL-6, IL-10, tumor necrosis factor (TNF)-α and interferon gamma (IFN-γ) using multiplex cytometric bead assays. The lower limit of quantification (LLOQ) is 125 pg/mL and the limit of detection (LOD) is 20 pg/mL.

Amgen Research (Munich) GmbH

Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.

Blinatumomab 15 μg

Blinatumomab 5/15 μg

Blinatumomab 5/15/30 μg

All participants who received blinatumomab by continuous intravenous infusion during the core study.

Blinatumomab Overall

Total

Age, Continuous

Sex: Female, Male

Race (NIH/OMB)

Number of Prior Relapses

Primary Refractory

Relapsed

Relapsed / refractory Status

Yes, Sibling

Yes, Unrelated

Yes, Haploidentical (mother/father)

No prior allogeneic HSCT

Prior Allogeneic Hematopoietic Stem cell Transplantation (HSCT)

Study Director

Participants received blinatumomab as a continuous intravenous infusion at a constant flow rate over 4 weeks followed by a 2-week treatment-free interval for up to 5 consecutive cycles.

Full analysis set (FAS), defined as participants who received any infusion of the assigned study medication, who completed at least the first treatment cycle and for whom at least one response assessment was available after the start of treatment.

Percentage of Participants With a Best Response of Complete Remission or Complete Remission With Only Partial Hematological Recovery Within 2 Cycles of Treatment

ABlinatumomab 5/15/30 μg

Percentage of Participants With a Best Response of Complete Remission Within 2 Cycles of Treatment

Percentage of Participants With a Best Response of Complete Remission With Only Partial Hematological Recovery Within 2 Cycles of Treatment

Percentage of Participants With a Best Response of Partial Remission Within 2 Cycles of Treatment

Percentage of Participants With a Minimal Residual Disease (MRD) Response During the Core Study

Percentage of Participants Who Received an Allogeneic Hematopoietic Stem Cell Transplant (HSCT) After Treatment With Blinatumomab

Blinatumimab Overall

Participants who reached complete remission or complete remission with partial hematological recovery during the core study.

Time to Hematological Relapse

Relapse-free Survival

Overall Survival

Any adverse event (AE)

Adverse events of at least CTC grade 3

Treatment-related adverse events

Related adverse events of at least CTC grade 3

Serious adverse events

Serious adverse events of at least CTC grade 3

Serious related adverse events

AEs leading to interruption of blinatumomab

AEs leading to discontinuation of blinatumomab

AEs leading to death

Safety analysis set, defined as all participants who received any infusion of blinatumomab.

Number of Participants With Treatment-emergent Adverse Events

Participants receiving blinatumomab 5 μg/m²/day.

Blinatumomab 5 μg

Participants receiving blinatumomab 15 μg/m²/day.

Participants receiving blinatumomab 30 μg/m²/day.

Blinatumomab 30 μg

Participants who received blinatumomab and who had available pharmacokinetic data.

Steady State Blinatumomab Concentration

All participants who received blinatumomab.

Clearance of Blinatumomab

IL-6: Cycle 1 (N=35)

IL-6: Cycle 2 (N=22)

IL-6: Cycle 3 (N=11)

IL-10: Cycle 1 (N=35)

IL-10: Cycle 2 (N=22)

IL-10: Cycle 3 (N=11)

IFN-Ɣ: Cycle 1 (N=35)

IFN-Ɣ: Cycle 2 (N=22)

IFN-Ɣ: Cycle 3 (N=11)

IL-2: Cycle 1 (N=35)

IL-2: Cycle 2 (N=22)

IL-2: Cycle 3 (N=11)

TNF-α: Cycle 1 (N=35)

TNF-α: Cycle 2 (N=22)

TNF-α: Cycle 3 (N=11)

Participants who received blinatumomab and who had evaluable pharmacodynamic data.

Serum Cytokine Peak Levels

Overall Study

Bortezomib

Antineoplastic Agents, Immunological

Immunologic Factors

to test whether adding rituximab in CD20 positive patients will have improvement in remission rate. (this arm terminated in October 2020) to add bortezomib in high risk patients at Induction to improve remission rate.

Bortezomib: patients with BM relapsed, add for 4 doses on D1,4,7, 11 in induction; dosage 1.3 mg/m2/dose as per parenteral;

Bortezomib Injection

Add rituximab in patients with CD20 positive ALL, rituximab: 6 doses of on D8,11of induction, D1,15 of consolidation1 and 2 with dosage 375 mg/m2 as parenteral (Terminated in Oct 2020)

rituximab injection

Chi Kong LI, Professor

Relapsed acute lymphoblastic leukaemia (ALL) has a poorer outcome than newly diagnosed ALL patients with only about 40% overall survival after re-treatment. The study CCCG Relapsed ALL 2017 study will adopt the UK R3 study stratification and treatment backbone with two new agents added. There will be a 4-week induction, followed by two consolidation courses. High-risk patients will receive allogeneic stem cell transplant. While intermediate and standard risk groups will continue maintenance treatment for another 2 years or one year. New agents will be added aiming at improving survival outcome.

1. Study of adding anti-CD20 antibody (rituximab) with chemotherapy: CD20 is found to be expressed in 40-50% of B-lineage ALL, and rituximab has been studied in adult ALL with superior survival (75% vs 47%,). There is little experience of using rituximab in pediatric ALL thus a CCCG Relapsed ALL 2017 Study will perform the study assessing the remission rate and MRD response of CD20+ ALL treated with rituximab. Six doses of rituximab and will be monitored the week 5 MRD and relapse rate as study outcome.

   (This arm was terminated in October 2020 after interim analysis showing lack of efficacy)
2. Adding bortezomid during the induction: The very early or early bone marrow relapse has low remission rate. Previous case studies showed that Bortezomib, a proteasome inhibitor, may achieve remission in refractory ALL, 80% remission in B-ALL with combination of chemotherapy and bortezomib. Thus adding bortezomib, may improve the remission rate, thus bridging to allogeneic stem cell transplant. Adding bortezomib in the relapsed chemotherapy protocol may increase the toxicity and even treatment related mortality. In this protocol, we suggested to add during the induction therapy.

Acute Lymphoblastic Leukemia (ALL) is now having over 80% event-free survival after frontline chemotherapy treatment. There is still 15-20% of patients having a relapse after initial control. Relapsed ALL is associated with lower second remission rate and also high chance of further relapse. Currently there are only a few large scale studies targeting this challenging disease. BFM Relapsed ALL studies have been organized since 1990s and have identified several important prognostic factors, including timing and site of relapse and also immunophenotyping. COG has performed several studies on relapsed ALL (AALL02P2, AALL0433, ADVL04P2) but the results are rather fragmented. Recently UK group conducted a nationwide randomized study, ALL R3 study, testing the type of anthracycline and prognostic value of minimal residual disease after induction therapy.

T-ALL relapse is having poor prognosis except for the late isolated extramedullary relapse. Long-term survival of T-ALL bone marrow relapse treated with chemotherapy is less than 10%, thus allogeneic stem cell transplant is always indicated. Whereas B-ALL has been better studied and the risk stratification of relapsed ALL is better defined.

According to previous studies, patients can be stratified into Standard, Intermediate and High-Risk groups based on site of relapse, time of relapse from first diagnosis and immunophenotyping. Early bone marrow relapse at less than 18-36 months from diagnosis is having the worst prognosis and is classified as HR. Those with late relapse at \>36 months from diagnosis is in general having a better prognosis. Bone marrow relapse is having a poorer outcome as compared to isolated extramedullary relapse (IEM). Somehow combined marrow and extramedullary relapse appear to have a better prognosis than isolated bone marrow relapse. Early B-ALL marrow relapse was only having 15-30% long-term survival, and early B-ALL IEM around 30-50% survival.

Late B-ALL marrow relapse has a higher second remission rate of around 95% and also better long term survival of 50-60%. Late B-ALL IEM is having a better prognosis of up to 70-80% survival. Based on the above criteria, several study groups including BFM, UK and COG also adopted similar strategies of stratifying patients and delivered risk-adapted treatment, with some minor variation among these groups.

Prospective and Non-randomized controlled trial

CCCG Relapsed Acute Lymphoblastic Leukemia 2017 Study in Children

Chinese Children Cancer Group Relapsed Acute Lymphoblastic Leukemia 2017 Study

bone marrow blast count \< 5% and MRD \<0.01%

survive without relapse or death or second cancer, with or without HSCT

Shanghai Children's Medical Center

Chinese University of Hong Kong

Professor

Symptoms and General Pathology

Recurrence

Childhood Acute Lymphoblastic Leukemia

Micronutrients

Hematinics

Vitamins

Hydrocortisone

Hydrocortisone 17-butyrate 21-propionate

Hydrocortisone acetate

Hydrocortisone hemisuccinate

BB 1101

Pegaspargase

Asparaginase

Glucocorticoids

Hormones

Hormone Antagonists

Antineoplastic Agents, Hormonal

Antimetabolites

Folic Acid

Vitamin B Complex

Folic Acid Antagonists

Immunosuppressive Agents

Antiviral Agents

Tubulin Modulators

Antimitotic Agents

Folinic Acid

Folate

Vitamin B9

Intervention: Bortezomib with chemotherapy (dexamethasone, PEG-asparaginase, doxorubicin, cytarabine, methotrexate, and vincristine) and Triple IT therapy for patients who are CNS 2 or 3 at study entry. 3+3 escalation design.

Intervention: Bortezomib with chemotherapy (dexamethasone, PEG-asparaginase, doxorubicin, cytarabine, methotrexate, and vincristine) and Triple IT therapy for patients who are CNS 2 or 3 at study entry. Patients receive bortezomib at maximum tolerated dose (as established in the Phase 1 portion of the study) and are assessed for response and toxicity.

Intravenous on days 1, 4, 8 and 11. Dose assigned at study entry.

10 mg/m2/day divided BID, oral administration for 14 days.

2500 IU/m2/day, intramuscular injection on Days 2, 8, 15 and 22

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
My-HyperCVAD in the Treatment of Relapsed Refractory Adult Acute Lymphoid Leukemia	NCT00801580	Lymphoid Leukem...	doxorubicin lip...	18 Years -	University of Bologna
Study of the BiTE® Blinatumomab (MT103) in Adult Patients With Relapsed/Refractory B-Precursor Acute Lymphoblastic Leukemia (ALL)	NCT01209286	B-ALL	Blinatumomab	18 Years -	Amgen Research (Munich) GmbH
CCCG Relapsed Acute Lymphoblastic Leukemia 2017 Study in Children	NCT04224571	Acute Lymphobla...	Bortezomib Inje... rituximab injec...	3 Months - 21 Years	Chinese University of Hong Kong
My-HyperCVAD in the Treatment of Relapsed Refractory Adult Acute Lymphoid Leukemia	NCT00801580	Lymphoid Leukem...	doxorubicin lip...	18 Years -	University of Bologna
Bortezomib With Chemotherapy for Relapsed Pediatric Acute Lymphoblastic Leukemia (ALL)	NCT00440726	Acute Lymphobla...	Bortezomib Dexamethasone PEG-asparaginas... Doxorubicin Cytarabine Methotrexate Vincristine Triple IT Thera...	1 Year - 21 Years	Therapeutic Advances in Childhood Leukemia Consortium
Clinical Study With Blinatumomab in Patients With Relapsed/Refractory B-precursor Acute Lymphoblastic Leukemia (ALL)	NCT01466179	Acute Lymphobla...	Blinatumomab	18 Years -	Amgen Research (Munich) GmbH
Study of the BiTE® Blinatumomab (MT103) in Adult Patients With Relapsed/Refractory B-Precursor Acute Lymphoblastic Leukemia (ALL)	NCT01209286	B-ALL	Blinatumomab	18 Years -	Amgen Research (Munich) GmbH
PR104 in Treating Patients With Refractory/Relapsed Acute Leukemia	NCT01037556	Acute Myelogeno... Acute Lymphocyt...	PR104	18 Years -	Proacta, Incorporated

Spots Global Cancer Trial Database for relapsed all

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