Neoplasms

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Leukemia, Lymphoid

Neoplasms by Histologic Type

Lymphoproliferative Disorders

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Dexamethasone

Hydrocortisone

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Hydrocortisone acetate

Hydrocortisone hemisuccinate

Cytarabine

Mitoxantrone

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Bortezomib

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Velcade will be given IV push on days 1,4,8 and 11 at a dose of 1.3 mg/m2/dose. At least 72 hours must have relapsed between doses.

IT Methotrexate (CNS Negative patients only) on days 1 and 8; age based dosing IT Methotrexate/Hydrocortisone/AraC (CNS positive patients only) on days 1, 8, 15 and 22; age based dosing.

Dexamethasone: Days 1-5 and 15-19; 10mg/m2/dose PO BID. Mitoxantrone: Days 1 and 2; 10mg/m2/dose Vincristine: days 1, 8, 15, and 22 at 1.5 mg/m2 (Maximum dose 2 mg) PEG-asparaginase: Days 3 and 17, 2500 IU/m2/dose

Velcade

Intrathecal dose For CNS negative patients, Day 1 and Day 8

Intrathecal dose for CNS positive patients, Day 1, 8, 15, 22

Methotrexate / Hydrocortisone / Cytarabine

Keith J August, MD

This is a phase II study designed to investigate the combination of bortezomib with the mitoxantrone reinduction regimen used in the ALL R3 trial. The study will enroll patients with high risk ALL relapse including early bone marrow relapse and second or greater relapse of any kind. Patients with relapsed LL will also be eligible. Bone marrow evaluation will be performed after blood counts recover to assess the rate of CR (\<5% bone marrow blasts) and MRD status in children following this regimen. Further treatment with or without HSCT will be at the discretion of the primary physician.

1.0 GOALS AND OBJECTIVES (SCIENTIFIC AIMS)

1.1 Primary Aims

1.1.1 To evaluate the feasibility and toxicity of using bortezomib in combination with the ALL R3 re-induction regimen in pediatric patients with relapsed or refractory ALL or LL.

1.1.2 To determine the rate of complete response and negative minimal residual disease status following bortezomib combined with R3 reinduction.

2.0 BACKGROUND

Despite the progress that has been made in the treatment of ALL in children, relapse of disease remains a significant treatment problem. By itself, the number of patients with relapsed ALL would be the 4th most common childhood malignancy and overall survival in these patients is poor. Using conventional treatments, second remission rates after bone marrow relapse in ALL are 81-93% and long-term event free survival (EFS) is only 27-50%. Initial standard therapy for children following relapse includes a four drug reinduction strategy, typically using prednisone, vincristine, PEG-asparaginase, and doxorubicin. For children with first marrow relapse of ALL less than 36 months from diagnosis, this four drug reinduction strategy results in a CR rate of 68%. However, 75% of patients in CR2 had minimal residual disease (MRD) that was positive (\>0.01%) at the end of reinduction. The presence of MRD in relapsed ALL is strongly associated with worse long term outcomes. For children with ALL that relapsed following a second (CR2) remission, outcomes are dismal with 5 year disease free survival of 15%.

In 2010, results were published of the ALL R3 trial from the Children's Cancer and Leukemia Group in the United Kingdom and Ireland. This trial randomized children with first relapse of ALL to receive a four drug reinduction using either mitoxantrone or idarubicin as the anthracycline. The study was closed early due to a statistically significant improvement in survival for children randomized to mitoxantrone. Children who received mitoxantrone had a 3 year disease free survival of 64.6% compared to 35.9% in the idarubicin group. Toxicities in this study were not excessive, and children randomized to receive mitoxantrone had significantly less toxicity than those in the idarubicin group. Based on the results of this trial, the Children's Oncology Group (COG) has begun using this reinduction regimen as the backbone for new clinical trials for children with relapsed ALL.

Despite the improvement in outcomes for the children with relapsed ALL treated with mitoxantrone on the R3 study, there is still a need for continued efforts to improve outcomes in patients with ALL and LL that experience a relapse. This is particularly true for high risk groups such as those who have an early bone marrow relapse (\<36 months from diagnosis), second or greater relapse or relapsed LL where long term survival remains less than 50% Bortezomib is a proteasome inhibitor that has demonstrated activity in a number of cancer types including acute leukemias. Bortezomib acts by inhibiting the ubiquitin-proteasome pathway resulting in the blockade of NF-κB activation and the stabilization of multiple proapoptotic proteins including p53, p21, p27, and Bax. Collectively, these effects induce apoptosis and enhance the cytotoxic effects of chemotherapy. In the Pediatric Preclinical Testing Program (PPTP), bortezomib showed activity against a number of ALL cell lines. As a single agent, bortezomib was effective at inhibiting NF-κB but there was no clinical response in 9 heavily pretreated children with ALL. Proteasome inhibition is able to induce apoptosis, and may be best utilized in combination with other conventional chemotherapy drugs to help overcome resistance. Preclinical evaluation of bortezomib with a number of drugs commonly used in pediatric ALL therapy demonstrated synergy with dexamethasone and additive effects when given along with vincristine, asparaginase, and doxorubicin.

In a phase 1 study of children with relapsed ALL of bortezomib combined with a four drug reinduction using dexamethasone, vincristine, doxorubicin, PEG-asparaginase and intrathecal therapy, bortezomib at a dose of 1.3 mg/m2 given on days 1, 4, 8 and 11 was well tolerated. The phase 2 study of this regimen was able to produce a complete response or complete response without platelet recovery in 73% of patients. These results are encouraging as these were heavily pretreated patients treated with 2 or 3 previous regimens. Due to 3 deaths from infectious toxicities, the study was amended to require infectious prophylaxis with vancomycin, levofloxacin, and voriconazole. No further deaths were seen in children following this change. Other toxicities seen on this study include grade 3 peripheral neuropathy in 2 patients.

This is a phase II study designed to investigate the combination of bortezomib with the mitoxantrone reinduction regimen used in the ALL R3 trial. The study will enroll patients with high risk ALL relapse including early bone marrow relapse and second or greater relapse of any kind. Patients with relapsed LL will also be eligible. Bone marrow evaluation will be performed after blood counts recover to assess the rate of CR (\<5% bone marrow blasts) and MRD status in children following this regimen. Further treatment with or without HSCT will be at the discretion of the primary physician.

2.1 Bortezomib for Injection 2.1.1 Scientific Background Bortezomib for Injection is a small-molecule proteasome inhibitor developed by Millennium Pharmaceuticals, Inc., (Millennium) as a novel agent to treat human malignancies. Bortezomib is currently approved by the United States Food and Drug Administration (US FDA) for the treatment of patients with multiple myeloma (MM). It is also indicated for the treatment of patients with mantle cell lymphoma (MCL) who have received at least 1 prior therapy. In the European Union (EU), bortezomib in combination with melphalan and prednisone is indicated for the treatment of patients with previously untreated MM who are not eligible for high-dose chemotherapy with bone marrow transplant. Bortezomib is indicated as monotherapy for the treatment of progressive MM in patients who have received at least 1 prior therapy and who have already undergone or are unsuitable for bone marrow transplantation.

By inhibiting a single molecular target, the proteasome, bortezomib affects multiple signaling pathways. The antineoplastic effect of bortezomib likely involves several distinct mechanisms, including inhibition of cell growth and survival pathways, induction of apoptosis, and inhibition of expression of genes that control cellular adhesion, migration, and angiogenesis. Thus, the mechanisms by which bortezomib elicits its antitumor activity may vary among tumor types, and the extent to which each affected pathway is critical to the inhibition of tumor growth could also differ. Bortezomib has a novel pattern of cytotoxicity in National Cancer Institute (NCI) in vitro and in vivo assays.(19) In addition, bortezomib has cytotoxic activity in a variety of xenograft tumor models, both as a single agent and in combination with chemotherapy and radiation. Notably, bortezomib induces apoptosis in cells that over express bcl-2, a genetic trait that confers unregulated growth and resistance to conventional chemotherapeutics.

The mechanisms of action leading up to apoptosis have been more clearly defined and include initiation of the unfolded protein response and direct/indirect effects on various molecular targets including cell cycle control proteins p27 and p21, cyclins, signal transduction molecules, transcription factors c-jun and HIF1-, tumor suppressor protein p53, angiogenesis factors, and many others. Bortezomib is thought to be efficacious in multiple myeloma via its inhibition of nuclear factor B (NF-B) activation, its attenuation of interleukin-6 (IL-6)-mediated cell growth, a direct apoptotic effect, and possibly anti-angiogenic and other effects.

Four Drug Reinduction With Bortezomib for Relapsed or Refractory ALL or LL in Children and Young Adults

A Pilot Study of Mitoxantrone-Based Four Drug Reinduction in Combination With Bortezomib for Relapsed or Refractory Acute Lymphoblastic Leukemia or Lymphoblastic Lymphoma in Children and Young Adults

Toxicities were assessed and graded according to CTCAE v 4.0.

Number of patients with bone marrow blast percentage \<5% after treatment

Percent of Cells Positive for Minimal residual disease measured by multiparameter flow cytometry

Millennium Pharmaceuticals, Inc.

Children's Mercy Hospital Kansas City

Principal Investigator

Velcade will be given IV push on days 1,4,8 and 11 at a dose of 1.3 mg/m2/dose. At least 72 hours must have relapsed between doses.

IT Methotrexate (CNS Negative patients only) on days 1 and 8; age based dosing IT Methotrexate/Hydrocortisone/AraC (CNS positive patients only) on days 1, 8, 15 and 22; age based dosing.

Dexamethasone: Days 1-5 and 15-19; 10mg/m2/dose PO BID. Mitoxantrone: Days 1 and 2; 10mg/m2/dose Vincristine: days 1, 8, 15, and 22 at 1.5 mg/m2 (Maximum dose 2 mg) PEG-asparaginase: Days 3 and 17, 2500 IU/m2/dose

Velcade: 4 doses of study drug will be given.

Methotrexate: Intrathecal dose For CNS negative patients, Day 1 and Day 8

Methotrexate / Hydrocortisone / Cytarabine: Intrathecal dose for CNS positive patients, Day 1, 8, 15, 22

Dexamethasone: Days 1-5 and 15-19

Mitoxantrone: Days 1 and 2

Vincristine: Days 1, 8, 15, 22

Pegaspargase: Days 3 and 17

Treatment Arm

Age, Categorical

Age, Continuous

Sex: Female, Male

Race (NIH/OMB)

United States

Region of Enrollment

Dr. Keith August

Number of Subject With Adverse Events

Remission Rate Seen With Using Bortezomib in Combination With the ALL R3 Re-induction Regimen in Pediatric Patients With Relapsed or Refractory ALL or LL.

Post-induction Level of Minimal Residual Disease Seen With Using Bortezomib in Combination With the ALL R3 Re-induction Regimen in Pediatric Patients With Relapsed or Refractory ALL or LL.

2-year Overall Survival Seen With Using Bortezomib in Combination With the ALL R3 Re-induction Regimen in Pediatric Patients With Relapsed or Refractory ALL or LL.

Overall Study

Heart and Blood Diseases

Multiple Myeloma

Neoplasms, Plasma Cell

Hemostatic Disorders

Blood Coagulation Disorders

Vascular Diseases

Paraproteinemias

Blood Protein Disorders

Hemorrhagic Disorders

Antibodies

Antibodies, Bispecific

Immunoglobulins

Muromonab-CD3

Phase 1 has two parts. Part 1, consists of REGN5458/linvoseltamab intravenous (IV) dose escalation and Part 2, consists of subcutaneous (SC) administration.

Note: subcutaneous (SC) administration is not applicable for US.

Low Dose of REGN5458/linvoseltamab IV monotherapy.

High Dose of REGN5458/linvoseltamab IV monotherapy.

Anti-interleukin (IL)-6 receptor (R) prophylactic therapy followed by high dose of IV dose of REGN5458 monotherapy.

Note: Cohort 3 is not applicable for US.

Linvoseltamab

Clinical Trial Administrator

Ka Lung Wu, MD

Marie-Christiane Vekemans, MD

Toshiki Uchida

Shinsuke Lida

Hiroshi Handa

Kunihiro Tsukasaki

Tadao Ishida

Mitsuo Hori

Junya Kuroda

Shuji Ozaki

Hyeon Seok Eom

Ja Min Byun, MD

Jin Seok Kim, MD

Chang Ki Min, MD

Paula Rodriguez Otero

Jordi Lopez Pardo, MD

Adrian Alegre Amor

Ana Jimenez Ubieto, MD

Joaquin Martinez Lopez, MD

Maria Victoria Mateos Manteca, MD

Martin Kaiser, MD

Clinical Trial Management

The main purpose of this study is to learn about the safety of REGN5458 and to find out what is the best dose of REGN5458 to give to patients with multiple myeloma. An additional purpose is to look for any signs that REGN5458 can treat cancer.

The study is looking at several other research questions, including:

* Side effects that may be experienced by people receiving REGN5458
* How REGN5458 works in the body
* How much REGN5458 is present in the blood
* How REGN5458 may work to treat cancer

Phase 1/2 Study of REGN5458 in Adult Patients With Relapsed or Refractory Multiple Myeloma

Phase 1/2 FIH Study of REGN5458 (Anti-BCMA x Anti-CD3 Bispecific Antibody) in Patients With Relapsed or Refractory Multiple Myeloma

All IPD that underlie results in a publication.

Phase 1 and Phase 2 for Japanese cohort only

Phase 1 Note: Phase 1, part 2 is not applicable for US.

Phase 1, part 2 and Phase 2, for Japanese cohort only

Phase 2, cohort 3 Note: Phase 2, Cohort 3 is not applicable for US.

Phase 1 part 1 and Phase 2 Note: Phase 2, Cohort 3 is not applicable for US.

Phase 1 and Phase 2 Note: Phase 1, part 2 and Phase 2, Cohort 3 is not applicable for US.

Phase 1 and Phase 2, cohorts 1 and 2 Note: Phase 1, part 2 is not applicable for US.

Phase 2 Note: Phase 2, Cohort 3 is not applicable for US.

Phase 2

The EORTC-QLQ-C30 is a 30-item subject self-report questionnaire composed of both multi-item and single scales, including global health status/quality of life, functional Scales (physical, role, emotional, cognitive, and social), symptom scales (fatigue, nausea and vomiting, and pain), and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). Participants rate items on a 4-point scale, with 1 as "not at all" and 4 as "very much."

Note: Phase 2, Cohort 3 is not applicable for US.

Phase 2

The EORTC QLQ-MY20 is a self -administered instrument to assess QoL in persons with MM. This 20-item questionnaire measures the following domains: symptom scales, including disease symptoms (6 items) and symptoms related to side effects of treatment (10 items); function scale and future perspective (3 items); and body image (1 item). A high score represents a high level of symptoms or problems.

Note: Phase 2, Cohort 3 is not applicable for US.

Phase 2

The EQ-5D-3L is a self-administered generic standardized health status measure, consisting of an EQ-5D descriptive system and an EQ visual analog scale. The EQ-5D-3L descriptive system assesses 5 dimensions of health: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension is rated on a 3-level scale: no problems, some problems, and extreme problems. The EQ visual analog scale component is a vertical visual analog scale used by patients to rate their health.

Note: Phase 2, Cohort 3 is not applicable for US.

Regeneron Pharmaceuticals

Leukemia, Myeloid

Leukemia, Myeloid, Acute

Hematologic Neoplasms

Myeloproliferative Disorders

Bone Marrow Diseases

Myeloid Leukemia

Acute Myeloid Leukemia

Acute Non Lymphoblastic Leukemia

Chronic Myeloproliferative Disorders

Dendritic Cell Tumor

Blastic Plasmacytoid Dendritic Cell

Escalation: IMGN632 was administered by IV on 2 different schedules for participants with relapsed/refractory AML, ALL, or BPDCN.

Expansion: IMGN632 was administered by IV:

* Cohort 1: Relapsed or refractory BPDCN participants who have received 1-3 prior systemic therapies (incl. tagraxofusp-erzs and/or any other systemic therapy deemed appropriate for the treatment of BPDCN)
* Cohort 2: Relapsed AML
* Cohort 3: Relapsed or refractory ALL
* Cohort 4: Other relapsed or refractory hematologic malignancies
* Cohort 5: Relapsed or refractory AML at alternate dose or schedule
* Cohort 6: Pivotal cohort for frontline BPDCN participants who have not received prior systemic therapy and participants with frontline BPDCN who have prior or concomitant hematologic malignancy (PCHM) and have not received prior systemic therapy.

IMGN632

Patrick Zweidler-McKay, MD

This is an open-label, multi-center, Phase 1/2 study to determine the MTD and assess the safety, tolerability, PK, immunogenicity, and anti-leukemia activity of IMGN632 when administered as monotherapy to patients with CD123+ disease.

IMGN632 is administered by IV on Day 1 of each cycle, with cycles repeating every 21 days.

Study of IMGN632 in Patients With Untreated BPDCN and Relapsed/Refractory BPDCN

A Phase 1/2, Multi-center, Open-label Study of IMGN632 Monotherapy Administered Intravenously in Patients With CD123-positive Acute Myeloid Leukemia and Other CD123-positive Hematologic Malignancies

Conversion rate to independence of red blood cell (RBC) and platelet transfusion relative to baseline

ImmunoGen, Inc.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Four Drug Reinduction With Bortezomib for Relapsed or Refractory ALL or LL in Children and Young Adults	NCT02535806	Acute Lymphobla... Lymphoblastic L...	Velcade Methotrexate Methotrexate / ... Dexamethasone Mitoxantrone Vincristine Pegaspargase	1 Year - 39 Years	Children's Mercy Hospital Kansas City
Phase 1/2 Study of REGN5458 in Adult Patients With Relapsed or Refractory Multiple Myeloma	NCT03761108	Multiple Myelom...	Linvoseltamab	18 Years -	Regeneron Pharmaceuticals
Study of IMGN632 in Patients With Untreated BPDCN and Relapsed/Refractory BPDCN	NCT03386513	Blastic Plasmac... Myeloproliferat...	IMGN632	18 Years -	ImmunoGen, Inc.
Four Drug Reinduction With Bortezomib for Relapsed or Refractory ALL or LL in Children and Young Adults	NCT02535806	Acute Lymphobla... Lymphoblastic L...	Velcade Methotrexate Methotrexate / ... Dexamethasone Mitoxantrone Vincristine Pegaspargase	1 Year - 39 Years	Children's Mercy Hospital Kansas City

Spots Global Cancer Trial Database for relapsed, refractory