Neoplasms

All Conditions

Rare Diseases

Glioma

Neoplasms, Neuroepithelial

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Glandular and Epithelial

Neoplasms, Nerve Tissue

Neuroepithelioma

Antineoplastic Agents

All Drugs and Chemicals

Temozolomide

Autologous bone marrow derived ALD-451 cells administered intravenously following surgery, radiation therapy and temozolomide

ALD-451

Annick Desjardins, MD

1. Purpose of the Study - This protocol aims to demonstrate the feasibility and safety of autologous ALD-451 cells administered intravenously in World Health Organization (WHO) grade IV malignant glioma patients following surgery, radiation therapy and temozolomide; as well as to obtain an initial description of the effects of ALD-451 cells on neuro-cognition allowing the design of a subsequent phase 2 trial of this intervention in patients with malignant glioma. The primary objective of this study is to demonstrate the safety of intravenously administered autologous bone marrow derived ALD-451 cells in the brain following surgery, radiation therapy and temozolomide in patients with WHO grade IV malignant glioma. The secondary objective of this study is to determine the recovery of ALD-451 from bone marrow of patients following radiation therapy and temozolomide. The exploratory objective of this study is to determine if intravenous administration of autologous ALD-451 cells following surgery, radiation therapy and temozolomide in WHO grade IV malignant glioma patients may have an effect on subsequent deterioration of neurocognition and patient-reported outcomes.

This is a pilot, open label study in which eligible subjects will undergo surgery, radiation therapy, Temozolomide, bone marrow harvest, MRIs, and intravenous infusion of ALD-451. The subjects will be followed via the safety and efficacy procedures completed during visits over 12 months.

Two to 8 weeks following gross total resection (GTR), patients with WHO grade IV malignant glioma that have agreed to participate in the study by signing the informed consent will undergo screening procedures to determine eligibility. Once enrolled on the study, baseline neurocognitive testing will be performed. Two to 8 weeks after enrolled subjects have completed the 6 -6 ½ weeks of radiation therapy and daily temozolomide, subjects will have their bone marrow harvested by undergoing a bone marrow aspiration with 160 (+/-20) mL of bone marrow collected from the iliac crest (one to 2 days after the patient has been re-assessed for continued eligibility).

The sample will be transported to the Robertson CT2 GMP Facility where ALD-451 will be manufactured and the ALD-451 product returned to the Investigational Chemotherapy Services for infusion. A small aliquot of ALD-451 will be taken from the starting bone marrow, de-identified, labeled with the manufacturing lot number, and stored at Duke University for the duration of the trial to support ongoing studies determining potency of the product. For all ALD-451 products, a retained aliquot that is the equivalent of 10 mls of the starting bone marrow will be cryopreserved and stored in the vapor phase of liquid nitrogen. Harvest of 160 mL of subject bone marrow will allow for retains without excessive reduction in the anticipated ALDHbr dose. These frozen retains will be used for product characterization and development of a potency assay. These aliquots will not be used for any other purposes and any remaining aliquots will be destroyed at the time of Biologics License Application (BLA) approval.

Two - four days after having bone marrow harvested for ALDHbr cells, ALD-451 will be administered through a peripheral IV, up to 1 hour. This will be followed by 4 hours of IV fluids and observation. Normal Saline will be used as the IV fluids and will be initiated a few minutes before the administration of ALD-451. The bag within which ALD-451 will be received will be flushed once with 10 ml of Normal Saline and the fluid obtained after flushing the bag will be administered to the patient, to assure that the investigators have reinfused in the patient the vast majority of the ALD-451 present in the bag.

Temozolomide will be reinitiated four weeks after completion of radiation therapy and daily Temozolomide (at least two weeks after ALD-451 infusion). Temozolomide will be dosed at 150 mg/m2 orally on days 1-5 of a 28-day cycle for the first cycle and 200 mg/m2 orally for the following 11 cycles. Patients will receive a total of 12 cycles of Temozolomide following completion of radiation therapy.

Neurocognitive testing and patient-reported outcomes will be obtained at study enrollment, two weeks after completion of radiation therapy and temozolomide and after six and twelve cycles of temozolomide.

Pilot Study of Bone Marrow/Stem Cells in Grade IV Malignant Glioma

A Pilot Safety Study of the Administration of Bone Marrow Derived Stem Cells (ALD-451) in WHO Grade IV Malignant Glioma

Number of patients with irreversible Grade 3 or greater central nervous system (CNS) toxicity or Grade 3 or greater non-hematologic toxicity if attributable to ALD -451

Henry Friedman

Professor of Pediatrics

Nervous System Diseases

Glioblastoma

Brain Neoplasms

Gliosarcoma

Astrocytoma

Bevacizumab

Proteasome Inhibitors

Antineoplastic Agents, Immunological

Angiogenesis Inhibitors

Growth Inhibitors

Part1-Phase1: MRZ 10 minute IV infusion on Days 1, 8, and 15 plus BEV IV infusion on Days 1 and 15 of each 28-day cycle.

Part2-Phase2: MRZ 10 minute IV infusion administered on Days 1, 8, and 15 of each 28-day cycle.

Part3-Phase2: All subjects will receive IV MRZ infusion and IV BEV infusion. MRZ will be administered as a 10-minute, IV infusion on Days 1, 8, and 15 of every 28-day cycle using intra-patient dose escalation. Starting dose will be 0.8 mg/m2.

Part4- Phase1: All subjects will receive MRZ enterally by NG tube as a bolus on Days 1, 8 and 15 of the first 28-day cycle and BEV IV infusion on Day 15 of the first 28-day cycle. For subsequent 28-day treatment cycles, MRZ will be administered as an IV at the recommended dose and schedule determined in Part 1, with BEV IV on Days 1 and 15.

Part5-Phase1: All subjects will receive IV MRZ infusion and IV BEV infusion. MRZ will be administered as a 10-minute, IV infusion at 0.8 mg/m2 on Days 1, 8, and 15 of every 28-day cycle 0.8 mg/m2

MRZ dosing in Phase 1 to range from 0.55 to 0.8 mg/m2. Dose Escalation: MRZ dose-escalation will occur using a standard 3+3 study design.

The RP2D of MRZ (0.8.mg/m2) will be used in a two stage design, with fifteen response-evaluable patients entered in the first stage. If 1 or more responses are observed at the MRZ RP2D, then the second stage will be implemented with an additional 15 response-evaluable patients treated.

BEV 10 mg/kg IV infusion administered for all cohorts in Phase 1 only.

Ileana Elias, MD

This is a Phase 1/2 clinical trial to evaluate a new combination of drugs, marizomib (MRZ) and bevacizumab (BEV; Avastin®), for the treatment of WHO Grade IV malignant glioma. The study population includes subjects who are in first or second relapse and who have not previously received any bevacizumab or other anti-angiogenic agent or proteasome inhibitor for treatment of malignant glioma. Part 1 Phase 1 evaluates the combination of MRZ and BEV, while Part 2 Phase 2 evaluates single-agent MRZ. Part 3 (Phase 2) includes a combination MRZ using intra-patient dose escalation, and BEV at a fixed dose. Part 4 Phase 1 evaluates MRZ through enteral administration, and BEV at a fixed dose. Part 5 Phase 1 evaluates the repeat-dose pharmacokinetics of MRZ administered IV with ECG.

One of the few treatment options currently FDA approved for recurrent WHO Grade IV malignant glioma is BEV. Additional treatment options are needed for these subjects. Published literature indicates that targeting the proteasome in glioma cells has shown significant anti-tumor activity.

MRZ is a novel, second generation proteasome inhibitor that prevents the breakdown of proteins involved in signal transduction which blocks growth and survival of cancer cells. In-vitro studies of multiple glioma cell lines were highly sensitive to MRZ. MRZ had relatively little effect on neural stem/progenitor cells suggesting minimal neurotoxicity while significantly affecting both malignant glioma stem cells and glioma cell lines.

Parts 1 and 2 of this trial have been completed with the Recommended Part 3 (Phase 2) Dose established at 0.8 mg/m2. Part 3 of this trial is enrolling at the MRZ RP2D determined in Phase 1 to assess the combination of MRZ and BEV activity and safety.

Parts 1, 2, 3 and 4 of this trial have been completed with the Recommended Dose established at 0.8 mg/m2. Part 5 of this trial is enrolling.

Stage 1: Marizomib + Bevacizumab in WHO Gr IV GBM; Stage 2: Marizomib Alone; Stage 3: Combination of Marizomib and Bevacizumab

Phase 1, Multicenter, Open-label, Dose-escalation, Combination Study of Marizomib and Bevacizumab in Bevacizumab-Naïve Subjects With WHO Grade IV Malignant Glioma Followed by Phase 2 Studies of Single Agent Marizomib and Combination Marizomib and Bevacizumab, and Phase 1 Dose-Escalation Study of Enterally-administered Marizomib With Bevacizumab

Radiographic ORR is defined as the percentage of participants achieving a Complete Response (CR) or Partial Response (PR), as assessed by the investigator, according to RANO 2010 criteria.

Tumor response assessment was conducted every 2 cycles of study therapy. 95% confidence interval from exact binomial distribution (Clopper-Pearson method).

OS is defined as time from the date of the first dose of study drug to date of death due to any cause. Participants who are alive will be censored at the last follow up visit

Number of subjects experiencing at least 1 Treatment-Emergent Adverse Event (TEAE) within the timeframe specified.

For Part 4, data are presented separately for Cycle 1 (when Marizomib was enterally-administered) and for Cycles 2 and subsequent cycles (when Marizomib was administered IV)

Number of subjects experiencing at least 1 Serious Adverse Event (SAE) within the timeframe specified.

For Part 4, data are presented separately for Cycle 1 (when Marizomib was enterally-administered) and for Cycles 2 and subsequent cycles (when Marizomib was administered IV)

Number of subjects experiencing at least 1 DLT event within the timeframe specified.

DLT is defined as the occurrence of any of the following AEs related to one of the drugs or the combination observed during Cycle 1, using NCI-CTCAE (v 4.03):

* ≥ Grade 3 thrombocytopenia or Grade 2 thrombocytopenia with bleeding.
* Grade 4 neutropenia or anemia lasting for more than 4 days.
* Febrile neutropenia.
* Any ≥ Grade 2 neurological event lasting more than 4 days.
* Grade 3 or 4 non-hematologic toxicity (excluding alopecia), lasting for more than 4 days despite adequate supportive therapy or preventing the next scheduled dose from being administered within 4 days of scheduled day; for ≥ Grade 3 fatigue to be considered a DLT, it must be present for more than 7 days.

For Part 4, data are presented separately for Cycle 1 (when Marizomib was enterally-administered) and for Cycles 2 and subsequent cycles (when Marizomib was administered IV).

DLT was assessed only for Part 1 and Part 4 cohorts.

Number of subjects experiencing at least 1 DLAE within the timeframe specified.

DLAEs are defined as Marizomib-related AEs observed which are:

* related to disturbances in the cerebellum (ie, ataxia, dizziness, dysarthria, fall, gait disturbances) plus hallucinations of any grade
* any other AEs of Grade ≥ 2. DLAEs were assessed only for Part 3 cohorts.

Radiographic ORR is defined as the percentage of participants achieving a Complete Response (CR) or Partial Response (PR), as assessed by the investigator, according to RANO 2010 criteria.

Tumor response assessment was conducted every 2 cycles of study therapy. 95% confidence interval from exact binomial distribution (Clopper-Pearson method).

Radiographic ORR was assessed for Part 1 and Part 3 cohorts

PFS is defined as the time between start of treatment and first evidence of documented disease progression or death (due to any cause), whichever occurs first. Disease progression will be determined using RANO 2010 criteria as assessed by the investigator.

PFS was determined using Kaplan-Meier product-limit estimates.

Triphase

Celgene

Marizomib 0.55 mg/m2 on Days 1,8, and 15 of each 28-day cycle + Bevacizumab 10 mg/Kg on Days 1 and 15 of each 28-day cycle

Part 1 Cohort 1

Marizomib 0.7 mg/m2 on Days 1,8, and 15 of each 28-day cycle + Bevacizumab 10 mg/Kg on Days 1 and 15 of each 28-day cycle

Part 1 Cohort 2

Marizomib 0.8 mg/m2 on Days 1,8, and 15 of each 28-day cycle + Bevacizumab 10 mg/Kg on Days 1 and 15 of each 28-day cycle.

MTD = Maximum Tolerated Dose

Part 1 MTD + Dose Expansion Cohort

Marizomib 0.8 mg/m2 on Days 1, 8, and 15 of each 28-day cycle

Part 2 Cohort

Marizomib 0.8 mg/m2 on Days 1,8, and 15 of each 28-day cycle + Bevacizumab 10 mg/Kg on Days 1 and 15 of each 28-day cycle. Based on presence of dose-limiting adverse events, participants did not escalate Marizomib to a dose of 1.0 mg/m2

Part 3 Cohort 1

Marizomib 0.8 mg/m2 on Days 1,8, and 15 of each 28-day cycle + Bevacizumab 10 mg/Kg on Days 1 and 15 of each 28-day cycle. Based on lack of dose-limiting adverse events for at least 1 cycle, participants were allowed to escalate Marizomib to a dose of 1.0 mg/m2

Part 3 Cohort 2

Marizomib 0.075 mg/m2 enterally-administered on Days 1,8, and 15 of each 28-day cycle + Bevacizumab 10 mg/Kg on Days 1 and 15 of each 28-day cycle. From Cycle 2, Marizomib was administered at a dose of 0.8 mg/m2 IV

Part 4 Cohort 1

Marizomib 0.225 mg/m2 enterally-administered on Days 1,8, and 15 of each 28-day cycle + Bevacizumab 10 mg/Kg on Days 1 and 15 of each 28-day cycle. From Cycle 2, Marizomib was administered at a dose of 0.8 mg/m2 IV

Part 4 Cohort 2

Marizomib 0.675 mg/m2 enterally-administered on Days 1,8, and 15 of each 28-day cycle + Bevacizumab 10 mg/Kg on Days 1 and 15 of each 28-day cycle. From Cycle 2, Marizomib was administered at a dose of 0.8 mg/m2 IV

Part 4 Cohort 3

Marizomib 1.0 mg/m2 enterally-administered on Days 1,8, and 15 of each 28-day cycle + Bevacizumab 10 mg/Kg on Days 1 and 15 of each 28-day cycle. From Cycle 2, Marizomib was administered at a dose of 0.8 mg/m2 IV

Part 4 Cohort 4

Marizomib 1.35 mg/m2 enterally-administered on Days 1,8, and 15 of each 28-day cycle + Bevacizumab 10 mg/Kg on Days 1 and 15 of each 28-day cycle. From Cycle 2, Marizomib was administered at a dose of 0.8 mg/m2 IV

Part 4 Cohort 5

Total

Age, Categorical

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

Bristol-Myers Squibb Study Director

All treated participants in Part 2 Cohort

Radiographic Objective Response Rate (ORR) - Part 2 Cohort

Overall Survival (OS) - Part 3 Cohorts

Marizomib 0.075 mg/m2 enterally-administered on Days 1,8, and 15 + Bevacizumab 10 mg/Kg on Days 1 and 15

Part 4 Cohort 1 - Cycle 1

Marizomib 0.225 mg/m2 enterally-administered on Days 1,8, and 15 + Bevacizumab 10 mg/Kg on Days 1 and 15

Part 4 Cohort 2 - Cycle 1

Marizomib 0.675 mg/m2 enterally-administered on Days 1,8, and 15 + Bevacizumab 10 mg/Kg on Days 1 and 15

Part 4 Cohort 3 - Cycle 1

Marizomib 1.0 mg/m2 enterally-administered on Days 1,8, and 15 + Bevacizumab 10 mg/Kg on Days 1 and 15

Part 4 Cohort 4 - Cycle 1

Marizomib 1.35 mg/m2 enterally-administered on Days 1,8, and 15 + Bevacizumab 10 mg/Kg on Days 1 and 15

Part 4 Cohort 5 - Cycle 1

Marizomib at different dosage IV-administered on Days 1,8, and 15 of each 28-day cycle + Bevacizumab 10 mg/Kg on Days 1 and 15 of each 28-day cycle

Part 4 All Cohorts - Cycles 2 and Subsequent

Number of Participants Experiencing Adverse Events

Number of Participants Experiencing Serious Adverse Events (SAEs)

All treated participants in Part 1 and Part 4

Number of Participants Experiencing Dose-Limiting Toxicity (DLT)

Number of Participants Experiencing Dose-Limiting Adverse Events (DLAEs)

All treated participants with available measurements

Radiographic Objective Response Rate (ORR)

Progression Free Survival (PFS)

Overall Survival (OS)

Overall Study

Symptoms and General Pathology

Recurrence

Pembrolizumab

Immune Checkpoint Inhibitors

Hypofractionated Stereotactic Irradiation (HFSRT). Pembrolizumab intravenous (IV) infusion every 3 weeks. Bevacizumab administered intravenously every 2 weeks.

Radiation therapy treatment (FSRT) which will be given to participants over 5 days.

Hypofractionated Stereotactic Irradiation (HFSRT)

Dose Escalation: The dose of pembrolizumab will be escalated per schema in a 3+3 fashion. The starting dose (i.e., dose level 1) will be 100 mg.

Dose Expansion: The pembrolizumab dose used in the dose expansion cohort will be maximum tolerated dose (MTD) determined from the dose escalation phase.

Initial cycle of bevacizumab must start within 10 days of registering to the trial. It will be given concurrent with radiation therapy. Bevacizumab will be administered intravenously at a dose of 10 mg/kg every 2 weeks. Doses will be adjusted if there is a \> 10% change in weight.

Solmaz Sahebjam, M.D.

The purpose of this study is to see if the addition of the investigation drug called pembrolizumab (Keytruda®) to radiation therapy and bevacizumab (Avastin®) is safe and can help with controlling the growth of tumors, in participants with recurrent high grade glioma.

Hypofractionated Stereotactic Irradiation (HFSRT) With Pembrolizumab and Bevacizumab for Recurrent High Grade Gliomas

A Phase I Trial of Hypofractionated Stereotactic Irradiation (HFSRT) With Pembrolizumab and Bevacizumab in Patients With Recurrent High Grade Gliomas

The pembrolizumab dose used in the dose expansion cohort will be MTD determined from the dose escalation phase. Dose Escalation: The maximum tolerated dose (MTD) is the highest dose of pembrolizumab in combination with bevacizumab after radiation therapy that does not cause unacceptable toxicity in more than one of six patients at that dose level. The MTD is defined as one dose level below the highest toxic dose (i.e., the Dose Limiting Toxicity (DLT) dose).

Response rate of pembrolizumab given in combination with bevacizumab and hypofractionated stereotactic re-irradiation of recurrent high grade gliomas. Response to treatment will be assessed by the investigator and according to the Response Assessment Criteria for High-Grade Gliomas (RANO Criteria). Brain MRI will be performed every 6 weeks beginning at the end of Week 6 (± 1 week) for 3 cycles and then every 12 weeks (± 1 week) until disease progression or treatment discontinuation, whichever occurs later.

Merck Sharp & Dohme LLC

H. Lee Moffitt Cancer Center and Research Institute

Hypofractionated Stereotactic Irradiation (HFSRT) radiation therapy treatment (FSRT) given to participants over 5 days. 100 mg Pembrolizumab intravenous (IV) infusion every 3 weeks. 10 mg/kg Bevacizumab administered intravenously every 2 weeks.

Dose Level 1: HFSRT With Pembrolizumab and Bevacizumab

Hypofractionated Stereotactic Irradiation (HFSRT) radiation therapy treatment (FSRT) given to participants over 5 days. 200 mg Pembrolizumab intravenous (IV) infusion every 3 weeks. 10 mg/kg Bevacizumab administered intravenously every 2 weeks.

Dose Level 2: HRSRT With Pembrolizumb and Bevacizumab

Participants Treated at Maximum Tolerated Dose

United States

Region of Enrollment

Peter Forsyth, MD

Hypofractionated Stereotactic Irradiation (HFSRT). Pembrolizumab intravenous (IV) infusion every 3 weeks. Bevacizumab administered intravenously every 2 weeks.

Hypofractionated Stereotactic Irradiation (HFSRT): Radiation therapy treatment (FSRT) which will be given to participants over 5 days.

Pembrolizumab: Dose Escalation: The dose of pembrolizumab will be escalated per schema in a 3+3 fashion. The starting dose (i.e., dose level 1) will be 100 mg.

Dose Expansion: The pembrolizumab dose used in the dose expansion cohort will be maximum tolerated dose (MTD) determined from the dose escalation phase.

Bevacizumab: Initial cycle of bevacizumab must start within 10 days of registering to the trial. It will be given concurrent with radiation therapy. Bevacizumab will be administered intravenously at a dose of 10 mg/kg every 2 weeks. Doses will be adjusted if there is a \> 10% change in weight.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Pilot Study of Bone Marrow/Stem Cells in Grade IV Malignant Glioma	NCT01639612	Grade IV Malign...	ALD-451	18 Years -	Duke University
Stage 1: Marizomib + Bevacizumab in WHO Gr IV GBM; Stage 2: Marizomib Alone; Stage 3: Combination of Marizomib and Bevacizumab	NCT02330562	Malignant Gliom... Glioblastoma	MRZ BEV	18 Years -	Celgene
Hypofractionated Stereotactic Irradiation (HFSRT) With Pembrolizumab and Bevacizumab for Recurrent High Grade Gliomas	NCT02313272	Malignant Gliom...	Hypofractionate... Pembrolizumab Bevacizumab	18 Years -	H. Lee Moffitt Cancer Center and Research Institute
Hypofractionated Stereotactic Irradiation (HFSRT) With Pembrolizumab and Bevacizumab for Recurrent High Grade Gliomas	NCT02313272	Malignant Gliom...	Hypofractionate... Pembrolizumab Bevacizumab	18 Years -	H. Lee Moffitt Cancer Center and Research Institute

Spots Global Cancer Trial Database for grade iv malignant glioma