Neoplasms

Blood and Lymph Conditions

All Conditions

Immune System Diseases

Rare Diseases

Leukemia

Precursor Cell Lymphoblastic Leukemia-Lymphoma

Leukemia, Lymphoid

Lymphoproliferative Disorders

Neoplasms by Histologic Type

Immunoproliferative Disorders

Lymphatic Diseases

Lymphoma

Hematologic Diseases

Acute Lymphoblastic Leukemia

Lymphoblastic Lymphoma

Acute Graft Versus Host Disease

Lymphosarcoma

All Drugs and Chemicals

Antineoplastic Agents

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

Nervous System Diseases

Recurrence

Glioblastoma

Brain Neoplasms

Disease Progression

Astrocytoma

Glioma

Neoplasms, Neuroepithelial

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms, Glandular and Epithelial

Neoplasms, Nerve Tissue

Neuroepithelioma

Doxorubicin

Liposomal doxorubicin

Immunomodulating Agents

Mitogens

Panitumumab

EGFR(V)-EDV-Dox administered via 20 minute intravenous infusion once a week for seven weeks (1 Cycle). Subjects will receive one of two dose levels: 5 x 10\^9 or 8 x 10\^9. All subjects will undergo an adapted dose escalation regime in the first cycle of treatment. For subsequent cycles all doses will be administered at full strength (5x10\^9 or 8x10\^9 EGFR(V)-EDV-Dox). Subjects may receive further cycles of treatment if the tumor remains stable or is responding, and/or they are deriving clinical benefit from the therapy and are tolerating treatment.

EGFR(V)-EDV-Dox using EnGeneIC EDV™ technology is a bacterially derived minicell which packages a toxic payload, Doxorubicin, into a 400 nm particle which targets specific cancer cells using bispecific antibodies (BsAb). BsAb-targeted, payload-packaged EDV nanocells only exit the leaky blood vessels associated with tumors and enter into the tumor microenvironment. The BsAb binds to the tumor cell-surface receptor, where the EDV is taken up, broken down within the cancer cell and releases the Doxorubicin. The residual EDVs that do not make it into the tumor microenvironment, are engulfed by cells of the immune system and since the EDVs are derived from bacteria, they carry potent immuno-stimulating components which appear to bypass the immuno-suppression caused by the tumor.

EGFR(V)-EDV-Dox

Kelly Szajna, RN BSN

Whitney Webb, RN MSN CNRN

Tamika Wong, MPH

John A Boockvar, MD

Jennifer MacDiarmid, Ph.D

Himanshu Brahmbhatt, Ph. D

Gary L Gallia, M.D., Ph.D

Stuart A Grossman, M.D.

The purpose of the Cerebral EDV study is to determine the safety and tolerability of EGFR(V)-EDV-Dox in order to establish the best dose level to be used in future studies. The study will also examine the body's immune response to EGFR(V)-EDV-Dox and assess if it is effective in the treatment of patients with recurrent glioblastoma multiforme (GBM).

This is an open-label, Phase 1, dose exploration and preliminary immunogenicity study of single agent EGFR(V)-EDV-Dox in subjects with recurrent glioblastoma (GBM). Eligible subjects enrolled in the study will receive EGFR(V)-EDV-Dox administered weekly for 7 weeks via IV 20 minute infusion, followed by radiological evaluation at week 8 (1 Cycle). Subjects may continue to receive subsequent cycles of EGFR(V)-EDV-Dox unless the subject becomes intolerant to investigational product (IP), withdraw consent or the individual is no longer receiving clinical benefit (factors taken in to consideration will be disease progression radiologically or clinically, and clinical benefits to quality of life). Tumour assessment will be repeated after each 7 week cycle (week 8).

The study will take place in two parts, Part 1 (Dose Exploration) and Part 2 (Dose Expansion).

Part 1 - Dose Exploration will assess the safety and tolerability of multiple doses of drug at two dose levels (5 x 10\^9 and 8 x 10\^9) and will enroll prior to Part 2. Three subjects will be recruited per dose level. Enrollment will begin with the 5 x 10\^9 dose level, and the decision to enroll to the 8 x 10\^9 dose level will follow a comprehensive safety evaluation and a standard 3 + 3 dose escalation study design.

Part 2 - Dose Expansion will be conducted pending safety results of Part 1 to provide guidance regarding the recommended phase 2 dose (RP2D). Subjects will be treated and assessed as outlined in Part 1 above. If 0 out of 3 subjects, or 1 out of 6 subjects, experience dose limiting toxicities (DLTs) at the 5 x 10\^9 dose level in Part 1, additional subjects to a total of 10 will be recruited to this dose level in Part 2. Similarly, if 0 out of 3 subjects, or 1 out of 6 subjects, experience DLTs at the 8 x 10\^9 dose level in Part 1, additional subjects to a total of 10 will be recruited to this dose level in Part 2. If both dose levels are tolerated, a total of 10 subjects per dose level will be enrolled.

A safety follow-up visit must be performed 30 (+5) days after the last dose of drug for all subjects.All subjects who discontinue investigational product and who have not withdrawn full consent to participate in the study will continue in the long term follow-up phase. Long term follow-up will continue approximately every 1 month for 12 months, from the 30 (+5) day follow-up visit, then approximately every 2-3 months for the extent of subject survival.

A Study to Evaluate the Safety, Tolerability and Immunogenicity of EGFR(V)-EDV-Dox in Subjects With Recurrent Glioblastoma Multiforme (GBM)

A Phase 1 Study to Evaluate the Safety, Tolerability, and Immunogenicity of EGFR (Vectibix® Sequence)-Targeted EnGeneIC Dream Vectors Containing Doxorubicin (EGFR(V)-EDV-Dox) in Subjects With Recurrent Glioblastoma Multiforme (GBM)

Recording of adverse Events (AE's) and clinically significant changes in vital signs, physical and neurological examinations, cardiac tests, radiological imaging inc. CT scan (Day 27/28) and clinical laboratory tests.

Disease response will be measured by Magnetic Resonance Imaging (MRI) using Response Assessment in Neuro-Oncology (RANO).

Review of safety data for dose limiting toxicity (DLT) evaluable subjects.

Johns Hopkins University

Engeneic Pty Limited

Respiratory Tract (Lung and Bronchial) Diseases

Digestive System Diseases

Gland and Hormone Related Diseases

Carcinoma, Non-Small-Cell Lung

Lung Neoplasms

Pancreatic Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Endocrine Gland Neoplasms

Gastrointestinal Diseases

Pancreatic Diseases

Endocrine System Diseases

Pancreatic Cancer

Immunologic Factors

Immunoglobulin G

Immunoglobulins, Intravenous

Participants will receive intravenous infusion of 750 mg of zenocutuzumab (MCLA-128) (the recommended Phase 2 dose (RP2D)) every 2 weeks.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
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
A Study to Evaluate the Safety, Tolerability and Immunogenicity of EGFR(V)-EDV-Dox in Subjects With Recurrent Glioblastoma Multiforme (GBM)	NCT02766699	Glioblastoma Astrocytoma, Gr...	EGFR(V)-EDV-Dox	18 Years -	Engeneic Pty Limited
A Study of Zenocutuzumab (MCLA-128) in Patients With Solid Tumors Harboring an NRG1 Fusion (eNRGy)	NCT02912949	Solid Tumours H... NSCLC Harboring... Pancreatic Canc... NRG1 Fusion	zenocutuzumab (...	18 Years -	Merus N.V.
A Study of Zenocutuzumab (MCLA-128) in Patients With Solid Tumors Harboring an NRG1 Fusion (eNRGy)	NCT02912949	Solid Tumours H... NSCLC Harboring... Pancreatic Canc... NRG1 Fusion	zenocutuzumab (...	18 Years -	Merus N.V.
MCLA-117 in Acute Myelogenous Leukemia	NCT03038230	Acute Myelogeno... Acute Myeloid L...	MCLA-117 bispec...	18 Years -	Merus N.V.
A Study to Evaluate the Safety, Tolerability and Immunogenicity of EGFR(V)-EDV-Dox in Subjects With Recurrent Glioblastoma Multiforme (GBM)	NCT02766699	Glioblastoma Astrocytoma, Gr...	EGFR(V)-EDV-Dox	18 Years -	Engeneic Pty Limited
MCLA-117 in Acute Myelogenous Leukemia	NCT03038230	Acute Myelogeno... Acute Myeloid L...	MCLA-117 bispec...	18 Years -	Merus N.V.
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

Spots Global Cancer Trial Database for antibodies, bispecific