Effect of AT7519M Alone and AT7519M Plus Bortezomib in Patients With Previously Treated Multiple Myeloma

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Multiple Myeloma Research Consortium
Information provided by (Responsible Party):
Astex Pharmaceuticals
ClinicalTrials.gov Identifier:
NCT01183949
First received: August 17, 2010
Last updated: June 24, 2014
Last verified: June 2014
  Purpose

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.


Condition Intervention Phase
Multiple Myeloma
Relapsed Multiple Myeloma
Refractory Multiple Myeloma
Drug: AT7519M, Bortezomib
Phase 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by Astex Pharmaceuticals:

Primary Outcome Measures:
  • To evaulate the clinical efficacy of AT7519M alone or in combination with bortezomib [ Time Frame: until patient withdraws ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • To characterize the safety and tolerability of AT7519M alone or in combination in patients with previously treated MM [ Time Frame: until patient withdraws ] [ Designated as safety issue: Yes ]
  • To define the pharmacokinetic profile of AT7519M and bortezomib when administered alone or in combination [ Time Frame: 4 cycles ] [ Designated as safety issue: No ]
  • To identify the maximum tolerated dose of AT7519M in combination with bortezomib [ Time Frame: Until patient withdrawal ] [ Designated as safety issue: No ]

Enrollment: 18
Study Start Date: November 2010
Estimated Study Completion Date: March 2015
Estimated Primary Completion Date: December 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment
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.
Drug: AT7519M, Bortezomib

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.


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).

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01183949

Locations
United States, Massachusetts
Massachusetts General Hospital
Boston, Massachusetts, United States, MA02115
Dana Faber Cancer Institute
Boston, Massachusetts, United States
Beth Israel Deaconess Medical Center
Boston, Massachusetts, United States, 02215
United States, New York
Memorial Sloan-Kettering Cancer Centre
New York, New York, United States, 10065
United States, Wisconsin
MCW and Froedtert Clinical Cancer Center, Division of Neoplastic Diseases & Related Disorders
Milwaukee, Wisconsin, United States, 53226
Sponsors and Collaborators
Astex Pharmaceuticals
Multiple Myeloma Research Consortium
  More Information

No publications provided

Responsible Party: Astex Pharmaceuticals
ClinicalTrials.gov Identifier: NCT01183949     History of Changes
Other Study ID Numbers: AT7519M/0004
Study First Received: August 17, 2010
Last Updated: June 24, 2014
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board

Keywords provided by Astex Pharmaceuticals:
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

Additional relevant MeSH terms:
Multiple Myeloma
Neoplasms, Plasma Cell
Neoplasms by Histologic Type
Neoplasms
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases
Bortezomib
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions

ClinicalTrials.gov processed this record on August 25, 2014