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

Antineoplastic Agents

All Drugs and Chemicals

Anti-Infective Agents

Inotuzumab Ozogamicin

Antineoplastic Agents, Immunological

Anti-Bacterial Agents

Antibiotics, Antitubercular

Immunotoxins

Immunoconjugates

Immunologic Factors

Patients will receive up to 3 cycles Inotuzumab with applications on day 1, 8 and 15 in each cycle. First dose will be 0.8 mg/m² on Day 1. All subsequent doses will be 0,5 mg/m².

Patients will receive standard of care chemotherapy (only maintenance) after Inotuzumab Ozogamicin.

Inotuzumab ozogamicin

Matthias Stelljes (Principal Investigator), MD

Julian Knaden (Study Coordinator)

Andreas Rank, PD Dr

Katjana Schwab, Dr

Mathias Hänel, PD Dr

Nael Alakel, Dr.

Kathrin Nachtkamp, Dr

Bernd Spriewald, Prof

Maher Hanoun, PD Dr.

Nicola Gökbuget, Dr

Ralph Wäsch, Prof. Dr.

Simon Raffel, Dr

Sebastian Scholl, PD Dr

Matthias Stelljes, Prof Dr

Kerstin Schäfer-Eckhardt, Dr

Sonja Martin, Dr.

Matthias Stelljes, MD

The trial proposed to evaluate the efficacy and safety of an inotuzumab ozogamicin followed by maintenance treatment in patients with acute lymphoblastic leukemia older than 56 years

Despite recent advances especially in younger patients, the prognosis of elderly patients with ALL remains dismal with a 5-year survival rate of around 20%, even after intensive chemotherapy.

Inotuzumab ozogamicin (PF-05208773; CMC-544) is an antibody-targeted intravenous (IV) chemotherapy agent composed of an anti-CD22 antibody linked to calicheamicin, a potent cytotoxic antitumor antibiotic.

After a prephase treatment, induction therapy will be based on three cycles of inotuzumab ozogamicin and intrathecal therapy only. This will be followed by a conventional maintenance therapy. All patients will be followed for cytological response, minimal residual disease and safety parameters.

Inotuzumab Ozogamicin and Conventional Chemotherapy In Patients Aged 56 Years and Older With ALL

Open Label Phase II Study to Evaluate the Efficacy and Safety of Inotuzumab Ozogamicin for Induction Followed by Chemotherapy Consolidation and Maintenance Therapy In Patients Aged 56 Years and Older With Acute Lymphoblastic Leukemia (ALL)

An event is any of the following: persisting bone marrow blasts (more than 5% leukemic blasts) after two cycles of inotuzumab ozogamicin, relapse or death.

The rate of complete hematological remission after inotuzumab ozogamicin induction treatment

The rate of patients being negative for minimal residual disease (defined by RQ-PCR for at least one leukemia-specific IG/TR gene rearrangement or leukemia specific genetic aberration with a sensitivity of at least 10-4) after induction treatment

The proportion of patients with molecular relapse

Nicola Goekbuget

Head of GMALL

Antibodies

Antibodies, Bispecific

Immunoglobulins

Blinatumomab

Blinatumomab was administered as a continuous intravenous (cIV) infusion at a constant daily flow rate over 4 weeks followed by a treatment-free interval of 2 weeks. Doses ranged between 5 and 30 µg/m²/day. Each participant received up to five cycles of treatment.

Administered by continuous intravenous infusion

Arend von Stackelberg, MD

Lia Gore, MD

The purpose of this study is to determine the dose of the bispecific T cell engager blinatumomab (MT103) in pediatric and adolescent patients with relapsed/refractory acute lymphoblastic leukemia (ALL) and to assess whether this dose of blinatumomab is effective.

Childhood acute lymphoblastic leukemia (ALL) is a type of cancer of the blood and bone marrow in which the bone marrow makes too many abnormal immature lymphocytes.

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 cluster of differentiation (CD)19 expressing cells.

The purpose of this study is to investigate the pharmacokinetics (PK), pharmacodynamics (PD) and safety of escalating doses of blinatumomab in pediatric and adolescent patients with relapsed/refractory B-precursor ALL, to select a dose and to investigate the efficacy and safety of that dose of blinatumomab in the above-mentioned patient population.

The phase 1 part of the study included the evaluation of four dose levels of blinatumomab with comprehensive PK/PD assessments and was separated in 2 parts:

* Phase 1 dose evaluation/escalation part to define the recommended phase 2 dose of blinatumomab in patients aged 2 to 17 years
* Phase 1 PK expansion part in patients aged \< 18 years to further assess PK/PD at the recommended phase 2 dose. In this part additional participants were enrolled to ensure that 6 patients in each of the 2 older age groups (2-6 and 7-17 years) were analyzed for PK before recruitment of infants \< 2 years of age began.

In the phase 2 extension cohort (efficacy phase) of the study, eligible participants less than 18 years were enrolled according to a two-stage design and received blinatumomab at the recommended dose level (5/15 μg/m²/day).

The study consisted of a screening period, a treatment period, and an End of Core Study visit 30 days after last dose of study medication. A treatment cycle consisted of a continuous intravenous (cIV) infusion over 4 weeks followed by a treatment-free interval of 2 weeks. Participants who achieved complete remission (CR) within 2 cycles of treatment could receive up to 3 additional consolidation cycles of blinatumomab. Instead of consolidation cycles with blinatumomab, participants could be withdrawn from blinatumomab treatment to receive chemotherapy or allogeneic HSCT as early as the first cycle, at the discretion of the investigator.

After the last treatment cycle and End of Core Study visit, all participants were followed for efficacy and survival for up to 24 months after treatment start. Participants who suffered a hematological relapse of B-precursor ALL during their follow-up period (at least 3 months after completion of treatment) had the possibility for retreatment with blinatumomab.

Clinical Study With Blinatumomab in Pediatric and Adolescent Patients With Relapsed/Refractory B-precursor Acute Lymphoblastic Leukemia

A Single-Arm Multicenter Phase II Study Preceded by Dose Evaluation to Investigate the Efficacy, Safety, and Tolerability of the BiTE® Antibody Blinatumomab (MT103) in Pediatric and Adolescent Patients With Relapsed/Refractory B-Precursor Acute Lymphoblastic Leukemia (ALL)

The maximum tolerated dose (MTD) was defined as one or fewer out of 6 participants experiencing a dose limiting toxicity (DLT) or the maximum administered dose (MAD).

A dose limiting toxicity is any Grade ≥ 3 adverse event related to study drug, Grade 3 fatigue, headache, insomnia, fever, hypotension or infection were not considered dose limiting toxicities. Laboratory parameters of Grade ≥ 3 but not considered as clinically relevant and/or responding to routine medical management, thrombocytopenia, leukopenia (including neutropenia and lymphopenia), and anemia were not considered dose limiting toxicities.

Hematological assessments were performed from bone marrow biopsy samples. All hematological assessments of bone marrow were reviewed in a central laboratory. Complete remission (CR) was defined as

* M1 bone marrow (bone marrow blasts \< 5%)
* No evidence of circulating blasts or extra-medullary disease

Complete remission includes participants with incomplete recovery of peripheral blood counts.

The severity (or intensity) of adverse events (AEs) was assessed according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), v4.03 and according to the following:

Grade 1 - Mild adverse event; Grade 2 - Moderate adverse event; Grade 3 - Severe and undesirable adverse event; Grade 4 - Life-threatening or disabling adverse event; Grade 5 - Death. The investigator used medical judgment to determine if there was a causal relationship (ie, related, unrelated) between an adverse event and blinatumomab.

Blinatumomab serum concentrations were quantified in all patients during the first 2 treatment cycles in the phase 1 part of the study only. Blinatumomab concentrations were quantified using a validated bioassay, the lower limit of quantification was 50 pg/mL. Steady state serum concentration (Css) was presumed on day 1, approximately 5 half-lives after the start of the IV infusion.

The steady state serum concentration reported is the mean of the observed concentrations collected after during cycles 1 and 2.

Time to hematological relapse was measured only for participants in remission 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 date of death.

Hematological relapse is defined as the proportion of blasts in bone marrow \> 25% following documented remission, or extramedullary relapse.

Time to hematological relapse was analyzed by Kaplan-Meier methods and the median observation time was calculated by the reverse Kaplan Meier method.

Overall survival (OS) was measured for all participants from the first treatment of blinatumomab until death due to any cause or the date of the last follow-up. Participants who did not die were censored on the last documented visit date or the date of the last contact when the patient was last known to have been alive. For patients who withdrew their informed consent only information until the date of withdrawal was analyzed.

Overall survival was estimated using Kaplan-Meier methods. The median follow-up time with respect to overall survival was calculated by the reverse Kaplan-Meier method.

Relapse-free survival (RFS) was assessed for participants who achieved a complete remission 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 and the median observation time was calculated by the reverse Kaplan-Meier method.

The percentage of participants who received allogeneic hematopoietic stem cell transplantation (HSCT) while in remission due to treatment with blinatumomab during the first two cycles, and received no further anti-leukemic medication before HSCT.

Antibodies to blinatumomab were detected using an electrochemiluminescence (ECL)-based assay.

The activation of immune effector cells was monitored by the measurement of peripheral blood cytokine levels including interleukin (IL)-2, IL-4, IL-6, IL-10, tumor necrosis factor-alpha (TNF-α) and interferon gamma (IFN-ɣ) using cytometric bead assays. The limit of detection of the assay (LOD) was 20 pg/mL and the lower limit of quantification (LLOQ) was 125 pg/mL. Data below LOD were set to 10 pg/mL while data \< LOQ and \> LOD were reported as measured.

Amgen Research (Munich) GmbH

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

Blinatumomab was administered as a continuous intravenous infusion at a constant daily flow rate of 5 µg/m²/day over 4 weeks followed by a treatment-free interval of 2 weeks for up to five cycles of treatment.

Phase 1: Blinatumomab 5 µg/m²/Day

Blinatumomab was administered as a continuous intravenous infusion at a constant daily flow rate of 15 µg/m²/day over 4 weeks followed by a treatment-free interval of 2 weeks for up to five cycles of treatment.

Phase 1: Blinatumomab 15 µg/m²/Day

Blinatumomab was administered as a continuous intravenous infusion at a constant daily flow rate of 5 µg/m²/day for the first week of cycle 1 and then at 15 µg/m²/day for 3 weeks followed by a treatment-free interval of 2 weeks. Participants received subsequent cycles at 15 µg/m²/day for up to five cycles of treatment.

Phase 1+2: Blinatumomab 5/15 µg/m²/Day

Blinatumomab was administered as a continuous intravenous infusion at a constant daily flow rate of 15 µg/m²/day for the first week of cycle 1 and then at 30 µg/m²/day for 3 weeks followed by a treatment-free interval of 2 weeks. Participants received subsequent cycles at 30 µg/m²/day for up to five cycles of treatment.

Phase 1: Blinatumomab 15/30 µg/m²/Day

Blinatumomab was administered as a continuous intravenous infusion at a constant daily flow rate of 30 µg/m²/day over 4 weeks followed by a treatment-free interval of 2 weeks for up to five cycles of treatment.

Phase 1: Blinatumomab 30 µg/m²/Day

All Participants who received blinatumomab administered as a continuous intravenous infusion at a constant daily flow rate.

Total

Blinatumomab was administered as a continuous intravenous (cIV) infusion at a constant daily flow rate of 5 µg/m²/day over 4 weeks followed by a treatment-free interval of 2 weeks for up to five cycles of treatment.

Phase 1: Blinatumomab 5/15 µg/m²/Day

Phase 2: Blinatumomab 5/15 µg/m²/Day

< 2 years

2 - 6 years

7 - 17 years

Age, Customized

Gender

White

Asian

Black or African American

American Indian or Alaska native

Native Hawaiian or other Pacific islander

Other

Unknown

Race was not recorded for any patient from France and for two further patients.

Race/Ethnicity, Customized

Prior Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

Study Director

Participants in the Phase 1 dose evaluation/escalation part of the study

Phase I: Number of Participants With Dose-limiting Toxicities (DLTs)

Blinatumomab was administered as a continuous intravenous infusion at a constant daily flow rate of 5 µg/m²/ day for the first week of cycle 1 and then at 15 µg/m²/day for 3 weeks followed by a treatment-free interval of 2 weeks. Participants received subsequent cycles at 15 µg/m²/day for up to five cycles of treatment.

The full analysis set includes all participants who received any infusion of blinatumomab.

Percentage of Participants With Complete Remission in the First Two Cycles

Any adverse event (AE)

Adverse event of at least CTC grade 3

Serious adverse event (SAEs)

SAE of at least grade 3

AE leading to interruption of study drug

AE leading to discontinuation of study drug

Adverse event leading to death

Treatment-related adverse event (TRAE)

TRAE of at least CTC grade 3

Treatment-related serious adverse event

TRAE leading to discontinuation of study drug

TRAE leading to death

Number of Participants With Adverse Events

Cycle 1 (N = 27, 34, 7)

Cycle 2 (N = 3, 13, 5)

Blinatumomab was administered as a continuous intravenous infusion at a constant daily flow rate of 5 µg/m²/day.

Blinatumomab was administered as a continuous intravenous infusion at a constant daily flow rate of 15 µg/m²/day.

Blinatumomab was administered as a continuous intravenous infusion at a constant daily flow rate of 30 µg/m²/day.

Phase 1 participants with available blinatumomab concentration data

Steady State Concentration of Blinatumomab

Blinatumomab was administered as a continuous intravenous (cIV) infusion at a constant daily flow rate ranging from 5 to 30 µg/m²/day over 4 weeks followed by a treatment-free interval of 2 weeks for up to five cycles of treatment.

Phase 1: Blinatumomab

Full analysis set with complete remission

Time to Hematological Relapse (Duration of Response)

Overall Survival

Blinatumomab was administered as a continuous intravenous infusion at a constant daily flow rate ranging from 5 to 30 µg/m²/day over 4 weeks followed by a treatment-free interval of 2 weeks for up to five cycles of treatment.

Relapse-free Survival

Percentage of Participants Who Received an Allogeneic Hematopoietic Stem Cell Transplant During Blinatumomab Induced Remission

Number of Participants Who Developed Anti-blinatumomab Antibodies

IL-6: Cycle 1 Week 1 (N=31, 13, 5)

IL-6: Cycle 2 Week 1 (N=4, 14, 5)

IL-10: Cycle 1 Week 1 (N=31, 13, 5)

IL-10: Cycle 2 Week 1 (N=4, 14, 5)

IFN-ɣ: Cycle 1 Week 1 (N=31, 13, 5)

IFN-ɣ: Cycle 2 Week 1 (N=4, 14, 5)

IL-2: Cycle 1 Week 1 (N=31, 13, 5)

IL-2: Cycle 2 Week 1 (N=4, 14, 5)

TNF-α: Cycle 1 Week 1 (N=31, 13, 5)

TNF-α: Cycle 2 Week 1 (N=4, 14, 5)

IL-4: Cycle 1 Week 1 (N=0, 0, 0)

IL-4: Cycle 2 Week 1 (N=0, 0, 0)

Blinatumomab was administered as a continuous intravenous infusion at a constant daily flow rate of 5 µg/m²/day..

Phase 1 full analysis set participants with available data

Serum Cytokine Peak Levels

Dose Evaluation/Escalation: Blinatumomab was administered as a continuous intravenous (cIV) infusion at a constant daily flow rate of 5 µg/m²/day over 4 weeks followed by a treatment-free interval of 2 weeks for up to five cycles of treatment.

Dose Evaluation/Escalation: Blinatumomab was administered as a continuous intravenous infusion at a constant daily flow rate of 15 µg/m²/day over 4 weeks followed by a treatment-free interval of 2 weeks for up to five cycles of treatment.

Dose Evaluation/Escalation: Blinatumomab was administered as a continuous intravenous infusion at a constant daily flow rate of 30 µg/m²/day over 4 weeks followed by a treatment-free interval of 2 weeks for up to five cycles of treatment.

Dose Evaluation/Escalation: Blinatumomab was administered as a continuous intravenous infusion at a constant daily flow rate of 15 µg/m²/day for the first week of cycle 1 and then at 30 µg/m²/day for 3 weeks followed by a treatment-free interval of 2 weeks. Participants received subsequent cycles at 30 µg/m²/day for up to five cycles of treatment.

PK Expansion: Blinatumomab was administered as a continuous intravenous infusion at a constant daily flow rate of 5 µg/m²/day for the first week of cycle 1 and then at 15 µg/m²/day for 3 weeks followed by a treatment-free interval of 2 weeks. Participants received subsequent cycles at 15 µg/m²/day for up to five cycles of treatment.

Overall Study

Symptoms and General Pathology

Musculoskeletal Diseases

Nutritional and Metabolic Diseases

Syndrome

Osteoporosis

Metabolic Syndrome

Insulin Resistance

Hyperinsulinism

Metabolic Diseases

Glucose Metabolism Disorders

Bone Diseases

Bone Diseases, Metabolic

Childhood Acute Lymphoblastic Leukemia

Children and adolescents who have completed treatment of for acute lymphoblastic leukemia (ALL) and lymphoma.

Laura D Bilek, PhD

This project will examine habitual physical activity, bone health, and insulin resistance in pediatric acute lymphocytic leukemia (ALL) and lymphoma cancer survivors at two time points: baseline and 6 months. At the two study timepoints, all study participants will be asked to wear an accelerometer, receive a DXA scan of the lumbar spine and hip, and have blood drawn for analysis. Study participants will be given a gift card stipend for each study visit attended. Study visits will coincide with regular office visits to Children's Hospital Oncology Clinic and the Children's Hospital Survivorship Clinics whenever possible. The potential mechanism by which physical activity mediates bone changes will be explored by concurrently measuring changes in lean/fat mass and metabolic status. This pilot study will provide data to inform the design of a randomized controlled trial to test the effect of a physical activity intervention on bone health in PCS.

Childhood cancer treatments are increasingly effective, leading to dramatic improvements in survival rates. These treatments often have devastating effects on the overall health of pediatric cancer survivors (PCS) since they occur during a critical time of bone growth, including increased risks of poor bone health, fracture, and diabetes. In normal child development, physical activity habits influence bone density and structure, which affect bone strength in adulthood. Despite this well-understood principle of bone development, there are no exercise guidelines for improving bone health in PCS. The long-term goal of this research is to develop an effective exercise intervention to improve bone health after cancer therapy. As a first step, the investigators propose to test the hypothesis that the intensity and amount of ground impact of a child's daily physical activity will influence changes in bone density in PCS. The Specific Aims are to (1) examine the effect of physical activity on lumbar bone density of PCS and to (2) evaluate how physical activity influences bone density. In a prospective cohort study, the investigators will enroll 38 pediatric and adolescent survivors (ages 5-18) of acute lymphoblastic leukemia or lymphoma at any post-treatment time point. Aim 1: At two assessments, baseline and six months later, bone density and structure (by DXA scan, a type of x-ray that can measure bone density and the amount of muscle and fat in the body) and physical activity level (by accelerometry, a device like a fitness tracker) will be evaluated. Each child will be categorized as having low or high physical activity based on accelerometry measures averaged from baseline and six-month assessments. Bone changes (0-6 months) will be compared between low and high activity groups. Aim 2: Evaluate potential mechanisms by which physical activity mediates changes in bone, including the effects of lean mass (measured by DXA) and metabolic health (lipid panel, insulin sensitivity (HOMA-IR, hemoglobin A1c), vitamin D). Long-term impact: This research will provide information as to the types of exercise that impact bone health in PCS. This study will help develop effective, evidence-based exercise therapies. These therapies may help prevent fractures and associated disability, leading to an improvement in the quality of life for survivors of pediatric cancer.

Healthy Bones, Healthy Life: Habitual Physical Activity on Bone & Metabolic Health in Pediatric Cancer Survivors

Healthy Bones, Healthy Life: Effect of Habitual Physical Activity on Bone and Metabolic Health in Pediatric Cancer Survivors

z-score of lumbar Spine bone density- DXA scan

Physical Activity as measured by accelerometry

cholesterol (total, HDL, and LDL) and triglycerides will be measured, which are an indicator of overall cardiovascular health which can impact insulin sensitivity

Fasting Insulin and Fasting Glucose will be combined to calculate the HOMA-IR, which is an indicator of insulin sensitivity

measure of the glycated hemoglobin in blood, which is an indicator of insulin sensitivity

measures the levels of vitamin D in the blood which is an indicator of bone health

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Inotuzumab Ozogamicin and Conventional Chemotherapy In Patients Aged 56 Years and Older With ALL	NCT03460522	Precursor Cell ...	Inotuzumab ozog...	56 Years - 74 Years	Goethe University
Clinical Study With Blinatumomab in Pediatric and Adolescent Patients With Relapsed/Refractory B-precursor Acute Lymphoblastic Leukemia	NCT01471782	Acute Lymphobla...	Blinatumomab	- 17 Years	Amgen Research (Munich) GmbH
Healthy Bones, Healthy Life: Habitual Physical Activity on Bone & Metabolic Health in Pediatric Cancer Survivors	NCT04472286	Acute Lymphobla... Pediatric ALL Pediatric Lymph... Bone Loss Metabolic Syndr... Habitual Physic... Precursor Cell ... Lymphoma Leukemia Lymphoid Leukem... Pediatric Osteoporosis Osteoporosis Ri...		5 Years - 18 Years	University of Nebraska
Inotuzumab Ozogamicin and Conventional Chemotherapy In Patients Aged 56 Years and Older With ALL	NCT03460522	Precursor Cell ...	Inotuzumab ozog...	56 Years - 74 Years	Goethe University
Phase 3 Trial of Blinatumomab vs Standard Chemotherapy in Pediatric Subjects With HIgh-Risk (HR) First Relapse B-precursor Acute Lymphoblastic Leukemia (ALL)	NCT02393859	Leukemia, Acute...	Blinatumomab Dexamethasone Vincrisitne Daunorubicin Methotrexate Ifosfamide PEG-asparaginas... Erwinia-asparag...	0 Years - 17 Years	Amgen
Healthy Bones, Healthy Life: Habitual Physical Activity on Bone & Metabolic Health in Pediatric Cancer Survivors	NCT04472286	Acute Lymphobla... Pediatric ALL Pediatric Lymph... Bone Loss Metabolic Syndr... Habitual Physic... Precursor Cell ... Lymphoma Leukemia Lymphoid Leukem... Pediatric Osteoporosis Osteoporosis Ri...		5 Years - 18 Years	University of Nebraska

Spots Global Cancer Trial Database for precursor cell lymphoblastic leukemia