Patients will receive escalating doses (up to 5 planned) of CAR+ T cells infused on day 0 + Cyclophosphamide: 300 mg/m2 IV infusion over 30 minutes on days -5, -4 and -3 + Fludarabine: 30 mg /m^2 IV infusion over 30 minutes administered immediately following the cyclophosphamide on days -5, -4, and -3

6.0x10^6 dose (maximum feasible dose) of CAR T Cells + Cyclophosphamide: 300 mg/m2 IV infusion over 30 minutes on days -5, -4 and -3 + Fludarabine: 30 mg/m^2 IV infusion over 30 minutes administered immediately following the cyclophosphamide on days -5, -4, and -3

Myeloma-Multiple

Myeloma, Plasma-Cell

300 mg/m^2 IV over 30 minutes on days -5, -4, and -3

Cyclophosphamide

30 mg/m^2 IV infusion over 30 minutes administered immediately following the cyclophosphamide on day -5, -4, -3

Fludarabine

0.75x10^6 - 12.0X10^6 CAR+ T cells per kg of recipient bodyweight one time dose on day 0

Anti-BCMA CAR T cells

National Institutes of Health Clinical Center

T Cells Expressing a Novel Fully-Human Anti-BCMA CAR for Treating Multiple Myeloma

A Phase I Clinical Trial of T Cells Expressing a Novel Fully-human Anti-BCMA CAR for Treating Multiple Myeloma

National Cancer Institute (NCI)

Pre-treatment imaging
Pre-treatment questionnaires and laboratory blood samples
Intervention (Thermal ablation of bone metastasis with MR-HIFU device Philips Sonalleve coupled with Philips Ingenia 3.0T)
Follow-up (imaging, questionnaires, laboratory)
Follow-up pain medication usage

Pre-treatment imaging
Pre-treatment questionnaires and laboratory blood samples
Intervention (Varian Truebeam Radiotherapy System)
Follow-up (imaging, questionnaires, laboratory)
Follow-up pain medication usage

Bone Metastases

Bone Neoplasm

Bone Cancer

Bone Lesion

Procedure is performed under proper analgesia (general or local anesthesia). The intervention can be performed in areas accessible with ultrasound with no critical structures (nerves, vasculature, bowels) in proximity. Limbs and pelvis are most usually accepted locations.
Patient is adjusted on top of the HIFU-transducer connected to MRI. First a MR-scan is performed and the treatment procedure is planned on consol. Then under MRI-guidance a point by point ablation of the target tumor is performed. During the treatment a real-time thermometry is obtained in order to avoid unwanted heating of related structures and to observe sufficient effect on treatment zone. After treatment MR-scan with gadolinium is performed to evaluate the size of ablated area.

Thermal ablation of bone metastasis with MR-HIFU device Philips Sonalleve coupled with Philips Ingenia 3.0T

Conventional radiotherapy focused on bone tumor. Pretreatment planning images acquired with computer tomography

Varian Truebeam Radiotherapy System

MR Imaging- Guided High Intensity Focused Ultrasound (HIFU) Therapy of Bone Metastases

Change in Visual analog scale pretreatment vs follow-up

Changes in tumor features pretreatment vs follow-up (signs of progression or regression)

Change in the use of strong opiate-based pain medication intake pretreatment vs follow-up

Change in SF-36 questionnaire pretreatment vs follow-up. SF36 is translated in finnish. It measures several variables related to quality of life ( eg mood, need of help)

Change in serum inflammatory cytokines pretreatment vs follow-up

Change in serum tumor-specific markers (eg. PSA for prostate cancer patients) pretreatment vs follow-up

Possible adverse effects found during treatment or in follow up will be collected and reported

Possible collaboration in the future with Karolinska Institute, Stockholm, during later stages of the study when performing randomized experiments. Data to be shared would be MRI- and CT-data, laboratory results and health-questionnaire results.

Turku University Hospital

Potential participants are recruited by oncologist from oncology outpatient clinic. Pretreatment imaging with computer tomography and magnetic resonance imaging is performed to evaluate whether the patient is eligible for HIFU-treatment. Those eligible will continue to the treatment and unsuitable participants will continue in the study as a control group receiving radiation therapy.
Participants in these groups will have follow-up MRI:s, ct:s, laboratory exams and fill in VAS (visual analog scale) and health questionnaire SF-36 regularly. Also intake of pain medication will be followed.

Dose Escalation with 5 dose levels based on the patients actual bodyweight

Dose Escalation with 5 dose levels based on the patients actual bodyweight
Cyclophosphamide: 300 mg/m^2 intravenous (IV) over 30 minutes on days -5, -4, and -3
Fludarabine: 30 mg/m^2 intravenous (IV) over 30 minutes immediately following the cyclophosphamide on day -5, -4, and -3
Anti-B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T cells: 0.3x10^6- 15.0x10^6 CAR+ T cells per kg of recipient bodyweight one time dose on day 0

0.3 x 10^6 CAR-BCMA T-cells Infused

1 x 10^6 CAR-BCMA T-cells Infused

3 x 10^6 CAR-BCMA T-cells Infused

9 x 10^6 CAR-BCMA T-cells Infused

Total

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

Region of Enrollment

Dose limiting toxicities are defined as follows: Grade 3 toxicities possibly or probably related to either the anti-BCMA CAR T cells or the fludarabine and cyclophosphamide chemotherapy and lasting more than 7 days. Grade 4 toxicities possibly or probably related to the study interventions.

Number of Participants With Dose Limiting Toxicities

Here is the count of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.

Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0)

Best response was assessed by the International Myeloma Working Group response criteria. Partial Remission (PR) is 50% or greater reduction of serum M-protein and 90% or greater reduction in 24-h urinary M-protein. Progressive Disease (PD) is increases of greater or equal to 25% from the lowest post-treatment (nadir) value in serum M-component or urine component or percentage of bone marrow plasma cells. Definite development of new bone lesions or new plasmacytoma. Very Good Partial Remission (VGPR) is serum and urine M-protein detectable by immunofixation but not on electrophoresis. Stringent Complete Remission (sCR) is normal free light chain ratio and absence of clonal cells in bone marrow by immunohistochemistry. Complete Remission is negative immunofixation on the serum and urine. Stable Disease (SD) is not meeting criteria for CR, VGPR, PR or PD.

Number of Participants With Best Response

Overall Study

Dr. James N. Kochenderfer

300 mg/m^2 intravenous (IV) over 30 minutes on days -5, -4, and -3

30 mg/m^2 intravenous (IV) over 30 minutes immediately following the cyclophosphamide on day -5, -4, and -3

0.3x10^6- 15.0x10^6 CAR+ T cells per kg of recipient bodyweight one time dose on day 0

Anti-B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T cells

National Institutes of Health Clinical Center, 9000 Rockville Pike

Study of T Cells Targeting B-Cell Maturation Antigen for Previously Treated Multiple Myeloma

A Phase I Clinical Trial of T-Cells Targeting B-Cell Maturation Antigen for Previously Treated Multiple Myeloma

James Kochenderfer, M.D.

Principal Investigator

Multiple Myeloma

Carfilzomib

Universitätsklinikum Schleswig-Holstein (UKSH) - Division of Stem Cell Transplantation and Immunotherapy, 2nd Department of Medicine

Fo.NE.Sa. Onlus

Divisione di Ematologia A.O.U. Ospedali Riuniti Umberto I - G.M. Lancisi - G. Salesi di Ancona

Carfilzomib In Combination With Bendamustine And Dexamethasone In Refractory Or Relapsed Multiple Myeloma

CARFILZOMIB IN COMBINATION WITH BENDAMUSTINE AND DEXAMETHASONE IN REFRACTORY OR RELAPSED MULTIPLE MYELOMA - A MULTICENTER PHASE IB/II TRIAL OF THE EUROPEAN MYELOMA NETWORK TRIALIST GROUP (EMNTG)

DLTs are defined as the following:
Any CTCAE grade ≥3 non-hematologic event except the following:
1. Nausea or vomiting that responds symptomatic therapy.
Grade 4 neutropenia lasting more than 7 days.
Grade 4 hematologic toxicity except neutropenia
Development of febrile neutropenia defined as grade 3-4 neutropenia with fever 38.5°C and/or infection requiring antibiotic or antifungal treatment. Assessment of DLT defining adverse events will be performed after completion of the second cycle (only in phase Ib) according to the National Cancer Institute Common Terminology Criteria of Adverse Events (CTCAE version 4.0). Efficacy will be assessed by considering VGPR following the proposed regimen, according to the criteria of the International Myeloma Working Group

Determine the rate of very good partial response (VGPR) or more with the CBd association: a VGPR rate of 20% (p0) is considered not promising (H0) and a 40% (p1) as interesting (phase II).

plasmacytoma/koorts

T Cells Expressing a Novel Fully-Human Anti-BCMA CAR for Treating Multiple Myeloma

MR Imaging- Guided High Intensity Focused Ultrasound (HIFU) Therapy of Bone Metastases

Study of T Cells Targeting B-Cell Maturation Antigen for Previously Treated Multiple Myeloma

Carfilzomib In Combination With Bendamustine And Dexamethasone In Refractory Or Relapsed Multiple Myeloma

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