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Onalespib in Treating Patients With Relapsed or Refractory Anaplastic Large Cell Lymphoma, Mantle Cell Lymphoma, or Diffuse Large B-Cell Lymphoma

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ClinicalTrials.gov Identifier: NCT02572453
Recruitment Status : Recruiting
First Posted : October 9, 2015
Last Update Posted : December 11, 2017
Sponsor:
Information provided by (Responsible Party):

Study Description
Brief Summary:
This phase II trial studies how well onalespib works in treating patients with anaplastic large cell lymphoma, mantle cell lymphoma, or diffuse large B-cell lymphoma that has not responded to previous treatment or that has returned after a period of improvement. Onalespib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Condition or disease Intervention/treatment Phase
ALK Positive BCL6 Positive Recurrent Anaplastic Large Cell Lymphoma Recurrent Diffuse Large B-Cell Lymphoma Recurrent Mantle Cell Lymphoma Refractory Anaplastic Large Cell Lymphoma Refractory Diffuse Large B-Cell Lymphoma Refractory Mantle Cell Lymphoma Other: Laboratory Biomarker Analysis Drug: Onalespib Phase 2

Detailed Description:

PRIMARY OBJECTIVES:

I. Overall response rate (ORR) to single agent AT13387 (onalespib) as measured by the proportion of partial and complete responses (PR + CR) in patients with relapsed/refractory ALK positive (+) anaplastic large cell lymphoma (ALCL), mantle cell lymphoma (MCL), and BCL6+ diffuse large B cell lymphoma (DLBCL).

SECONDARY OBJECTIVES:

I. Progression free survival (PFS) and overall survival (OS), as well as duration of response (DOR) of single agent AT13387 (onalespib) in patients with ALK+ ALCL, MCL, and BCL6+ DLBCL.

II. Safety and tolerability of single agent AT13387 (onalespib) in patients with ALK+ ALCL, MCL, and BCL6+ DLBCL.

TERTIARY OBJECTIVES:

I. Measurement of on-target activity of AT13387 (onalespib) in ALK+ ALCL, MCL, and BCL6+ DLBCL through immunoblotting and immunohistochemistry of pre-treatment, on-treatment, and time of progression tumor biopsies for HSP90 clients.

II. Determination of genetic and transcriptional markers for response and resistance to AT13387 (onalespib) in patients with ALK+ ALCL, MCL, and BCL6+ DLBCL.

OUTLINE:

Patients receive onalespib intravenously (IV) over 1 hour on days 1, 2, 8, 9, 15, and 16. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 6 months for up to 1 year.


Study Design

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 50 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase 2 Study of AT13387 (Onalespib) in ALK+ ALCL, MCL, and BCL-6+ DLBCL
Actual Study Start Date : April 4, 2016
Estimated Primary Completion Date : August 31, 2019


Arms and Interventions

Arm Intervention/treatment
Experimental: Treatment (onalespib)
Patients receive onalespib IV over 1 hour on days 1, 2, 8, 9, 15, and 16. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Other: Laboratory Biomarker Analysis
Correlative studies
Drug: Onalespib
Given IV
Other Names:
  • AT 13387
  • AT-13387
  • AT13387


Outcome Measures

Primary Outcome Measures :
  1. Change in protein levels of ALK in ALK+ anaplastic large cell lymphoma via immunohistochemistry [ Time Frame: Baseline to up to 1 year after completion of study treatment ]
    Comparisons will be made between baseline, on treatment, and time of progression protein levels. An H-score will be used. Results at each time point and as changes as a proportion of baseline levels will be reported descriptively.

  2. Change in protein levels of BCL6 in diffuse large B cell lymphoma via immunohistochemistry [ Time Frame: Baseline to up to 1 year after completion of study treatment ]
    Comparisons will be made between baseline, on treatment, and time of progression protein levels and changes will be characterized as differences and as differences at the referenced time point as a proportion of baseline levels. An H-score will be used. The Wilcoxon rank sum test will be used to compare changes between responders and non-responders and a one-sided significance level will be used.

  3. Change in protein levels of cyclin D1 in mantle cell lymphoma via immunohistochemistry [ Time Frame: Baseline to up to 1 year after completion of study treatment ]
    Comparisons will be made between baseline, on treatment, and time of progression protein levels and changes will be characterized as differences and as differences at the referenced time point as a proportion of baseline levels. An H-score will be used. The Wilcoxon rank sum test will be used to compare changes between responders and non-responders and a one-sided significance level will be used.

  4. Objective response rate [ Time Frame: Up to 1 year after completion of study treatment ]
    Will be evaluated using the International Harmonization Project for lymphoma criteria.


Secondary Outcome Measures :
  1. Duration of response [ Time Frame: From first objective response (partial response or complete response) until the first date of documented progression or death due to any cause, assessed up to 1 year after completion of study treatment ]
    Duration of response will be evaluated only in patients who respond with either a partial response or complete response while on study.

  2. Incidence of toxicity, graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 [ Time Frame: Up to 1 year after completion of study treatment ]
    Toxicities will be summarized with counts and proportions within each cohort and overall.

  3. Overall survival [ Time Frame: From the date of study entry until the date of death by any cause, assessed up to 1 year after completion of study treatment ]
    The overall survival will be estimated by Kaplan-Meier method. Median follow-up time will be assessed using the reverse Kaplan-Meier method.

  4. Progression free survival [ Time Frame: From the date of study entry until documentation of first progression or death from any cause, assessed up to 1 year after completion of study treatment ]
    The progression free survival will be estimated by Kaplan-Meier method. Median follow-up time will be assessed using the reverse Kaplan-Meier method.


Other Outcome Measures:
  1. Genetic and transcriptional analysis for markers of response and resistance, via exome sequencing and ribonucleic acid sequencing [ Time Frame: Baseline to up to 1 year after completion of study treatment ]
    Absolute algorithm will be used to determine the cancer cell fraction.

  2. Onalespib activity, measured by changes in protein levels via immunoblotting [ Time Frame: Baseline to up to 1 year after completion of study treatment ]
    Will use a one-sided significance level.


Eligibility Criteria

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients must have histologically confirmed, relapsed/refractory ALK+ ALCL (with ALK positivity defined by immunohistochemistry and/or fluorescence in situ hybridization [FISH]/cytogenetics from any prior biopsy), MCL, or BCL6+ DLBCL (with BCL6 positivity defined by immunohistochemistry from any prior biopsy) and meet the following criteria:
  • Patients must have measurable disease that has not been previously irradiated, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >= 20 mm (>= 2 cm) with conventional imaging or >= 10 mm with spiral computed tomography (CT) scan; if the patient has been previously irradiated, there must be evidence of progression since the radiation

    • Please note, this trial includes mandatory tumor biopsies pre-treatment, during cycle 1 and at the time of disease progression of accessible tumor; having accessible tumor for biopsy is not required for eligibility; we expect that at least 80% of patients will have accessible tumor for these biopsies, however
  • ALK+ ALCL: patients must have disease that has relapsed and or is refractory to prior therapy, which must have included a multiagent chemotherapy regimen including an anthracycline, if not contraindicated, and prior brentuximab; prior crizotinib or other ALK inhibitor therapy, while recommended, is not mandatory; patients must have relapsed following or be ineligible for, or refuse, autologous stem cell transplant
  • MCL: patients must have disease that has relapsed and or is refractory to prior therapy, which must have included a multiagent chemotherapy regimen and prior ibrutinib or other BTK inhibitor therapy; patients must have relapsed following or be ineligible for, or refuse, autologous stem cell transplant
  • BCL6+ DLBCL: patients must have disease that has relapsed and or is refractory to prior therapy, which must have included an anthracycline, if not contraindicated; patients must have relapsed following or be ineligible for, or refuse, autologous stem cell transplant
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
  • Life expectancy of greater than 3 months
  • Absolute neutrophil count >= 1,000/mcL
  • Platelets >= 75,000/mcL, unless due to marrow involvement by lymphoma in which case a platelet count of >= 30,000/mcL will be used
  • Total bilirubin =< 1.5 x upper limit of normal (ULN), unless due to Gilbert's syndrome or hemolysis, in which case =< 3.0 x ULN is allowed
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional upper limit of normal
  • Creatinine =< 1.5 x ULN or a creatinine clearance >= 50 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal
  • Potassium above the institutional lower limit of normal (supplementation to meet this is allowed)
  • Magnesium above the institutional lower limit of normal (supplementation to meet this is allowed)
  • Human immunodeficiency virus (HIV)+ patients are eligible for the trial provided they meet the other study criteria in addition to the following:

    • CD4+ T-cells >= 250/mm^3
    • HIV sensitive to antiretroviral therapy
    • Zidovudine not allowed
    • Long term survival anticipated on the basis of HIV alone were it not for the lymphoma
    • No concurrent acquired immunodeficiency syndrome (AIDS)-defining illness other than the lymphoma
  • Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 4 months after the completion of AT13387 (onalespib) administration; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately; men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of AT13387 (onalespib) administration
  • Patients must be willing to not take St. John wort or grapefruit juice while participating in this trial and should avoid drugs that are strong inducers of P-gp, and to switch to alternative drugs when available
  • Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

  • Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier; steroids for symptom palliation are allowed, but must be either discontinued or on stable doses at the time of initiation of protocol therapy
  • Patients who are receiving any other investigational agents; all investigational agents other than ibrutinib must have been discontinued at least 4 weeks prior to beginning treatment; prior ibrutinib therapy must have been discontinued at least 2 weeks prior to beginning therapy
  • Patients with known leptomeningeal or brain metastases should be excluded from this clinical trial; imaging or spinal fluid analysis to exclude central nervous system (CNS) involvement is not required, unless there is clinical suspicion by the treating investigator
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to AT13387 (onalespib)
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements

    • There will be no exclusion of patients with known visual impairment or symptoms, including by not limited to peripheral flashes (photopsia), blurred or double vision, floaters, color distortion and dimness, difficulties with light/dark accommodation, tunnel vision or other field defects, halos, apparent movement of stationary objects, and complex disturbances; patients will have a baseline ophthalmologic exam to serve as a point of comparison and further exams as needed should visual symptoms develop; no pretreatment eye exam findings or ocular symptoms have been associated with an increased risk of ocular toxicity seen with AT13387
  • Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with AT13387 (onalespib)
  • Patients, who have had a major surgery or significant traumatic injury within 4 weeks of start of study drug, patients who have not recovered from the side effects of any major surgery (defined as requiring general anesthesia) or patients that may require major surgery during the course of the study
  • Prior history of another malignancy (except for non-melanoma skin cancer or in situ cervical or breast cancer) unless disease free for at least three years; patients with prostate cancer are allowed if prostate specific antigen (PSA) is less than 1
  • Patients should not receive immunization with attenuated live vaccine within one week of study entry or during study period
  • History of noncompliance to medical regimens
  • Consistent corrected QT (QTc) > 450 msec for men and > 470 msec for women by Fridericia formula, on 3 separate electrocardiograms (ECGs)
  • Left ventricular ejection fraction (LVEF) < 50%, regardless of whether there are symptoms of heart failure
Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02572453


Locations
United States, Kentucky
University of Kentucky/Markey Cancer Center Recruiting
Lexington, Kentucky, United States, 40536
Contact: Hayder Saeed    859-257-3379      
Principal Investigator: Hayder Saeed         
United States, Maryland
Johns Hopkins University/Sidney Kimmel Cancer Center Recruiting
Baltimore, Maryland, United States, 21287
Contact: Nina D. Wagner-Johnston    410-955-8804    jhcccro@jhmi.edu   
Principal Investigator: Nina D. Wagner-Johnston         
United States, Massachusetts
Brigham and Women's Hospital Recruiting
Boston, Massachusetts, United States, 02115
Contact: Caron A. Jacobson    888-823-5923    ctsucontact@westat.com   
Principal Investigator: Caron A. Jacobson         
Dana-Farber Cancer Institute Recruiting
Boston, Massachusetts, United States, 02215
Contact: Caron A. Jacobson    617-632-5847    cajacobson@partners.org   
Principal Investigator: Caron A. Jacobson         
United States, New Jersey
Rutgers Cancer Institute of New Jersey-Robert Wood Johnson University Hospital Recruiting
New Brunswick, New Jersey, United States, 08903
Contact: Kevin A. David    732-235-8675      
Principal Investigator: Kevin A. David         
Rutgers Cancer Institute of New Jersey Recruiting
New Brunswick, New Jersey, United States, 08903
Contact: Kevin A. David    732-235-8675      
Principal Investigator: Kevin A. David         
United States, Ohio
Ohio State University Comprehensive Cancer Center Recruiting
Columbus, Ohio, United States, 43210
Contact: Jonathan E. Brammer    800-293-5066    Jamesline@osumc.edu   
Principal Investigator: Jonathan E. Brammer         
United States, Pennsylvania
University of Pennsylvania/Abramson Cancer Center Active, not recruiting
Philadelphia, Pennsylvania, United States, 19104
University of Pittsburgh Cancer Institute (UPCI) Recruiting
Pittsburgh, Pennsylvania, United States, 15232
Contact: Kathleen A. Dorritie    412-647-8073      
Principal Investigator: Kathleen A. Dorritie         
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Principal Investigator: Caron Jacobson Dana-Farber - Harvard Cancer Center LAO
More Information

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT02572453     History of Changes
Other Study ID Numbers: NCI-2015-01681
NCI-2015-01681 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
15-XXX
16-712
9875 ( Other Identifier: Dana-Farber - Harvard Cancer Center LAO )
9875 ( Other Identifier: CTEP )
UM1CA186690 ( U.S. NIH Grant/Contract )
UM1CA186709 ( U.S. NIH Grant/Contract )
First Posted: October 9, 2015    Key Record Dates
Last Update Posted: December 11, 2017
Last Verified: November 2017

Additional relevant MeSH terms:
Lymphoma
Lymphoma, Non-Hodgkin
Lymphoma, B-Cell
Lymphoma, Mantle-Cell
Lymphoma, Large B-Cell, Diffuse
Lymphoma, Large-Cell, Anaplastic
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Lymphoma, T-Cell