Effect of AT7519M Alone and AT7519M Plus Bortezomib in Patients With Previously Treated Multiple Myeloma
Primary Purpose
Multiple Myeloma
Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
AT7519M
Bortezomib
Sponsored by
About this trial
This is an interventional treatment trial for Multiple Myeloma focused on measuring Neoplasms, Neoplasms, Plasma Cell, Neoplasms by Histologic Type, Hemostatic Disorders, Paraproteinemias, Blood Protein Disorders, Hematologic Diseases, Hemorrhagic Disorders, Lymphoproliferative Disorders, Immunoproliferative Disorders, Immune System Diseases, Bortezomib, Antineoplastic Agents
Eligibility Criteria
Inclusion Criteria:
- Ability to understand the risks of the study and provide signed informed consent
- Age 18 years or older
- Relapsed and or Refractory MM
- Disease progression following at least two systemic treatments for MM
- Patient must be refractory to the last bortezomib
- ECOG performance status 0, 1 or 2
Exclusion Criteria:
- Pregnant or lactating females. Patients of childbearing potential must use appropriate birth control throughout the study
- Inadequate liver function
- Renal impairment
- Neutrophil count <1.0 x 10^9 /litre in the absence of growth factors
- Platelet count <50 x 10^9 /litre in patients in whom <50% of bone marrow nucleated cells are plasma cells and <30 x 10^9 /litre in patients in whom ≥50 % of bone marrow nucleated cells are plasma cells
- Hemoglobin <8g/dl in the absence of transfusion
- Treated corrected calcium >ULN
- Serum creatine phosphokinase >ULN
- All previous cytotoxic therapies for MM must have been completed at least four weeks prior to treatment with AT7519M (two weeks for all non-cytotoxic therapy)
- Patients may be receiving concomitant therapy with biphosphonates and low dose corticosteroids. Bisphosphonates doses should be stable for at least 30 days prior to study drug administration. Corticosteroids doses should be stable for at least 7 days prior to study treatment
- Prior peripheral stem cell transplant within 12 weeks
- Evidence of mucosal or internal bleeding and/or platelet transfusion refractory (unable to maintain a platelet count >50 x 10^9 /litre)
- Ongoing infection requiring treatment
- Previous radiotherapy within 2 weeks of the start of the study
- Having previously received treatment with a cyclin-dependent kinase or GSK3beta inhibitor
- Incomplete recovery from previous radiotherapy other than residual cutaneous effects or stable < Grade 2 gastrointestinal toxicity
- Prior radiotherapy to the head and neck region for head and neck tumors
- Previous malignancy, except for non-melanomatous skin carcinomas, in situ carcinomas or malignancies with low risk of recurrence.
- Any severe or uncontrolled systemic conditions (e.g. systemic infection) or current unstable or uncompensated respiratory or cardiac conditions which makes it undesirable for the patient to participate in the study or which could jeopardize compliance with the protocol
- Incomplete recovery from surgery other than stable < Grade 2 toxicity
- Peripheral neuropathy > Grade 2
- Abnormal left ventricular ejection fraction (< lower limit of normal for the institution for a patient of that age) on echocardiogram
- History of an ischemic cardiac event, including myocardial infarction within 3 months of study entry
- Congestive cardiac failure of ≥ grade 3 severity according to NYHA functional classification
- Unstable cardiac disease
- History or presence of bradycardia (≤60bpm), left bundle branch block, heart block, cardiac pacemaker or significant atrial tachyarrhythmias
- If the patient will receive bortezomib (Velcade) during part C of the study, concurrent treatment with any medication known strongly to inhibit or induce CYP3A4, CYP1A2 and CYP2C19 which cannot be discontinued at least two week prior to treatment with AT7519M (other than corticosteroids)
- Concurrent treatment with any medication that prolongs QT interval and may induce Torsades de Pointes and which cannot be discontinued at least two weeks prior to treatment with AT7519M
- Family or personal history of long QTc syndrome or ventricular arrhythmias including ventricular bigeminy
- Previous history of drug-induced QTc prolongation
- Screening 12-lead ECG with measurable QTc interval according to Fridericia's Correction of >450 msecs
- Screening 12-lead ECG with ST depression >1 mm in 2 or more leads or T wave inversion in 2 or more contiguous leads
- Prior history of infection with human immunodeficiency virus (HIV), known active hepatitis B or C viruses
- Diffuse infiltrative pulmonary or pericardial disease
- Known hypersensitivity to bortezomib, boron or any of the excipients of VelcadeTM
- Epilepsy or other convulsive disorder requiring active management
- Serious psychiatric illness, active alcoholism or drug addiction that may hinder or confuse follow up evaluation
Sites / Locations
- Beth Israel Deaconess Medical Center
- Massachusetts General Hospital
- Dana Faber Cancer Institute
- Memorial Sloan-Kettering Cancer Centre
- MCW and Froedtert Clinical Cancer Center, Division of Neoplastic Diseases & Related Disorders
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Treatment
Arm Description
Patients will be enrolled into 3 groups which will run sequentially. Groups A and B will receive AT7519M only, whereas Group C will receive AT7519M in combination with Bortezomib.
Outcomes
Primary Outcome Measures
To evaluate the clinical efficacy of AT7519M alone or in combination with bortezomib
Efficacy will be assessed using the International Multiple Myeloma Working Group (IMWG) Response Criteria
Secondary Outcome Measures
Assess the type, incidence and severity of clinically significant treatment emergent adverse events as assessed by National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) V 4.03
To define the pharmacokinetic profile of AT7519M and bortezomib when administered alone or in combination with bortezomib
The pharmacokinetic evaluation will include the calculation of plasma clearance and elimination phase half-life for AT7519M and bortezomib
To identify the maximum tolerated dose (MTD) of AT7519M in combination with bortezomib
The MTD will be based on the incidence of dose limiting toxicities
Full Information
NCT ID
NCT01183949
First Posted
August 17, 2010
Last Updated
January 13, 2020
Sponsor
Astex Pharmaceuticals, Inc.
Collaborators
Multiple Myeloma Research Consortium
1. Study Identification
Unique Protocol Identification Number
NCT01183949
Brief Title
Effect of AT7519M Alone and AT7519M Plus Bortezomib in Patients With Previously Treated Multiple Myeloma
Official Title
A Phase I/II Open-label Multicenter Study of AT7519M Alone and in Combination With Bortezomib in Patients With Previously Treated Multiple Myeloma
Study Type
Interventional
2. Study Status
Record Verification Date
January 2020
Overall Recruitment Status
Completed
Study Start Date
November 2010 (undefined)
Primary Completion Date
December 2014 (Actual)
Study Completion Date
March 2015 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Astex Pharmaceuticals, Inc.
Collaborators
Multiple Myeloma Research Consortium
4. Oversight
Data Monitoring Committee
No
5. Study Description
Brief Summary
The purpose of this study is to determine whether AT7519M alone or AT7519M plus bortezomib are effective treatments in patients with previously treated multiple myeloma.
Detailed Description
The clinical study AT7519M/0004 is an open-label multicenter study to investigate the efficacy of AT7519M alone and AT7519M in combination with bortezomib in patients with previously treated multiple myeloma (MM).
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Multiple Myeloma
Keywords
Neoplasms, Neoplasms, Plasma Cell, Neoplasms by Histologic Type, Hemostatic Disorders, Paraproteinemias, Blood Protein Disorders, Hematologic Diseases, Hemorrhagic Disorders, Lymphoproliferative Disorders, Immunoproliferative Disorders, Immune System Diseases, Bortezomib, Antineoplastic Agents
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
18 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Treatment
Arm Type
Experimental
Arm Description
Patients will be enrolled into 3 groups which will run sequentially. Groups A and B will receive AT7519M only, whereas Group C will receive AT7519M in combination with Bortezomib.
Intervention Type
Drug
Intervention Name(s)
AT7519M
Intervention Description
Part A: Nine patients will receive AT7519M as an intravenous infusion on days 1, 4, 8 and 11 of a three week cycle. The starting dose of AT7519M will be 21mg/m^2/dose and will be increased to 27mg/m^2/dose during subsequent cycles in the absence of AT7519M-related toxicities.
Part B: Amendment clarified there will be no further exploration of AT7519M as a monotherapy.
Part C: Amendment modified dose escalation to a conventional 3 + 3 design with a maximum total of 14 patients will be treated at the maximum tolerated dose.
Intervention Type
Drug
Intervention Name(s)
Bortezomib
Intervention Description
Part C will treat between 3-26 patients with a combination of bortezomib and AT7519M in a dose escalation design. The starting doses for the dose escalation are bortezomib 1 mg/m2 and AT7519M 14 mg/m2.
Primary Outcome Measure Information:
Title
To evaluate the clinical efficacy of AT7519M alone or in combination with bortezomib
Description
Efficacy will be assessed using the International Multiple Myeloma Working Group (IMWG) Response Criteria
Time Frame
Subjects with be followed until disease progression (an average of 4 cycles per subject. i.e an average of 84 days)
Secondary Outcome Measure Information:
Title
Assess the type, incidence and severity of clinically significant treatment emergent adverse events as assessed by National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) V 4.03
Time Frame
Subjects with be followed until disease progression (an average of 4 cycles per subject, i.e an average of approximately 84 days)
Title
To define the pharmacokinetic profile of AT7519M and bortezomib when administered alone or in combination with bortezomib
Description
The pharmacokinetic evaluation will include the calculation of plasma clearance and elimination phase half-life for AT7519M and bortezomib
Time Frame
2 cycles (i.e an average of 42 days)
Title
To identify the maximum tolerated dose (MTD) of AT7519M in combination with bortezomib
Description
The MTD will be based on the incidence of dose limiting toxicities
Time Frame
Subjects with be followed until disease progression (an average of 4 cycles per subject, i.e an average of approximately 84 days)
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Ability to understand the risks of the study and provide signed informed consent
Age 18 years or older
Relapsed and or Refractory MM
Disease progression following at least two systemic treatments for MM
Patient must be refractory to the last bortezomib
ECOG performance status 0, 1 or 2
Exclusion Criteria:
Pregnant or lactating females. Patients of childbearing potential must use appropriate birth control throughout the study
Inadequate liver function
Renal impairment
Neutrophil count <1.0 x 10^9 /litre in the absence of growth factors
Platelet count <50 x 10^9 /litre in patients in whom <50% of bone marrow nucleated cells are plasma cells and <30 x 10^9 /litre in patients in whom ≥50 % of bone marrow nucleated cells are plasma cells
Hemoglobin <8g/dl in the absence of transfusion
Treated corrected calcium >ULN
Serum creatine phosphokinase >ULN
All previous cytotoxic therapies for MM must have been completed at least four weeks prior to treatment with AT7519M (two weeks for all non-cytotoxic therapy)
Patients may be receiving concomitant therapy with biphosphonates and low dose corticosteroids. Bisphosphonates doses should be stable for at least 30 days prior to study drug administration. Corticosteroids doses should be stable for at least 7 days prior to study treatment
Prior peripheral stem cell transplant within 12 weeks
Evidence of mucosal or internal bleeding and/or platelet transfusion refractory (unable to maintain a platelet count >50 x 10^9 /litre)
Ongoing infection requiring treatment
Previous radiotherapy within 2 weeks of the start of the study
Having previously received treatment with a cyclin-dependent kinase or GSK3beta inhibitor
Incomplete recovery from previous radiotherapy other than residual cutaneous effects or stable < Grade 2 gastrointestinal toxicity
Prior radiotherapy to the head and neck region for head and neck tumors
Previous malignancy, except for non-melanomatous skin carcinomas, in situ carcinomas or malignancies with low risk of recurrence.
Any severe or uncontrolled systemic conditions (e.g. systemic infection) or current unstable or uncompensated respiratory or cardiac conditions which makes it undesirable for the patient to participate in the study or which could jeopardize compliance with the protocol
Incomplete recovery from surgery other than stable < Grade 2 toxicity
Peripheral neuropathy > Grade 2
Abnormal left ventricular ejection fraction (< lower limit of normal for the institution for a patient of that age) on echocardiogram
History of an ischemic cardiac event, including myocardial infarction within 3 months of study entry
Congestive cardiac failure of ≥ grade 3 severity according to NYHA functional classification
Unstable cardiac disease
History or presence of bradycardia (≤60bpm), left bundle branch block, heart block, cardiac pacemaker or significant atrial tachyarrhythmias
If the patient will receive bortezomib (Velcade) during part C of the study, concurrent treatment with any medication known strongly to inhibit or induce CYP3A4, CYP1A2 and CYP2C19 which cannot be discontinued at least two week prior to treatment with AT7519M (other than corticosteroids)
Concurrent treatment with any medication that prolongs QT interval and may induce Torsades de Pointes and which cannot be discontinued at least two weeks prior to treatment with AT7519M
Family or personal history of long QTc syndrome or ventricular arrhythmias including ventricular bigeminy
Previous history of drug-induced QTc prolongation
Screening 12-lead ECG with measurable QTc interval according to Fridericia's Correction of >450 msecs
Screening 12-lead ECG with ST depression >1 mm in 2 or more leads or T wave inversion in 2 or more contiguous leads
Prior history of infection with human immunodeficiency virus (HIV), known active hepatitis B or C viruses
Diffuse infiltrative pulmonary or pericardial disease
Known hypersensitivity to bortezomib, boron or any of the excipients of VelcadeTM
Epilepsy or other convulsive disorder requiring active management
Serious psychiatric illness, active alcoholism or drug addiction that may hinder or confuse follow up evaluation
Facility Information:
Facility Name
Beth Israel Deaconess Medical Center
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02215
Country
United States
Facility Name
Massachusetts General Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
MA02115
Country
United States
Facility Name
Dana Faber Cancer Institute
City
Boston
State/Province
Massachusetts
Country
United States
Facility Name
Memorial Sloan-Kettering Cancer Centre
City
New York
State/Province
New York
ZIP/Postal Code
10065
Country
United States
Facility Name
MCW and Froedtert Clinical Cancer Center, Division of Neoplastic Diseases & Related Disorders
City
Milwaukee
State/Province
Wisconsin
ZIP/Postal Code
53226
Country
United States
12. IPD Sharing Statement
Learn more about this trial
Effect of AT7519M Alone and AT7519M Plus Bortezomib in Patients With Previously Treated Multiple Myeloma
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