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R-(-)-Gossypol Acetic Acid With Lenalidomide and Dexamethasone in Treating Patients With Relapsed Symptomatic Multiple Myeloma

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ClinicalTrials.gov Identifier: NCT02697344
Recruitment Status : Suspended (per study design to temporarily close)
First Posted : March 3, 2016
Last Update Posted : October 31, 2018
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Mayo Clinic

Brief Summary:
This phase I/II trial studies the side effects and best dose of R-(-)-gossypol acetic acid when given together with lenalidomide and dexamethasone and to see how well it works in treating patients with multiple myeloma, also known as plasma cell myeloma, that has come back after a period of improvement or has gotten worse after treatment. R-(-)-gossypol acetic acid may stop the growth of cancer cells by recognizing certain proteins and stimulating programmed cell death. Lenalidomide may stimulate or suppress the immune system in different ways and stop cancer cells from growing. Drugs used in chemotherapy, such as dexamethasone, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving R-(-)-gossypol acetic acid with lenalidomide and dexamethasone may work better in treating patients with multiple myeloma.

Condition or disease Intervention/treatment Phase
Recurrent Plasma Cell Myeloma Drug: Dexamethasone Other: Laboratory Biomarker Analysis Drug: Lenalidomide Other: Pharmacological Study Drug: R-(-)-Gossypol Acetic Acid Phase 1 Phase 2

Detailed Description:

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose of R-(-)-gossypol acetic acid (AT-101) that can be combined with lenalidomide and dexamethasone in patients with relapsed symptomatic multiple myeloma (MM). (Phase I) II. To determine the overall response rate (partial response or better) of AT-101 when used in combination with lenalidomide and dexamethasone in patients with relapsed symptomatic MM. (Phase II)

SECONDARY OBJECTIVES:

I. To determine the progression free survival and overall survival among patients with relapsed symptomatic MM following treatment with AT-101 in combination with lenalidomide and dexamethasone.

II. To determine the toxicities associated with AT-101 in combination with lenalidomide and dexamethasone in patients with relapsed symptomatic MM.

TERTIARY OBJECTIVES:

I. Determine in vivo the anti-myeloma effect of AT-101 alone by assessing extent of decrease in M-protein (serum and/or urine) after 1 cycle of AT-101 alone.

II. Determine the pharmacodynamics effect of AT-101 in combination with lenalidomide and dexamethasone treatment on primary myeloma cell in vivo.

III. Explore potential mechanism of resistance to AT-101 in combination with lenalidomide and dexamethasone therapy and the role of B-cell CLL/lymphoma 2 (Bcl-2).

OUTLINE: This is a phase I dose-escalation study of R-(-)-gossypol acetic acid followed by a phase II study.

Patients receive R-(-)-gossypol acetic acid orally (PO) once a day (QD) on days 1-21. Beginning in course 2, patients also receive lenalidomide PO QD on days 1-21 and dexamethasone PO QD on days 1, 8, and 15. Treatment repeats every 28 days for 12 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for up to 3 years.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 63 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase 1/2 Trial of AT-101 in Combination With Lenalidomide and Dexamethasone in Patients With Relapsed Symptomatic Multiple Myeloma
Actual Study Start Date : April 14, 2017
Estimated Primary Completion Date : June 15, 2021
Estimated Study Completion Date : June 15, 2021


Arm Intervention/treatment
Experimental: Treatment (AT-101, lenalidomide, and dexamethasone)
Patients receive R-(-)-gossypol acetic acid PO QD on days 1-21. Beginning in course 2, patients also receive lenalidomide PO QD on days 1-21 and dexamethasone PO QD on days 1, 8, and 15 of courses 2-12. Treatment repeats every 28 days for 12 courses in the absence of disease progression or unacceptable toxicity.
Drug: Dexamethasone
Given PO
Other Names:
  • Aacidexam
  • Adexone
  • Aknichthol Dexa
  • Alba-Dex
  • Alin
  • Alin Depot
  • Alin Oftalmico
  • Amplidermis
  • Anemul mono
  • Auricularum
  • Auxiloson
  • Baycuten
  • Baycuten N
  • Cortidexason
  • Cortisumman
  • Decacort
  • Decadrol
  • Decadron
  • Decalix
  • Decameth
  • Decasone R.p.
  • Dectancyl
  • Dekacort
  • Deltafluorene
  • Deronil
  • Desamethasone
  • Desameton
  • Dexa-Mamallet
  • Dexa-Rhinosan
  • Dexa-Scheroson
  • Dexa-sine
  • Dexacortal
  • Dexacortin
  • Dexafarma
  • Dexafluorene
  • Dexalocal
  • Dexamecortin
  • Dexameth
  • Dexamethasonum
  • Dexamonozon
  • Dexapos
  • Dexinoral
  • Dexone
  • Dinormon
  • Fluorodelta
  • Fortecortin
  • Gammacorten
  • Hexadecadrol
  • Hexadrol
  • Lokalison-F
  • Loverine
  • Methylfluorprednisolone
  • Millicorten
  • Mymethasone
  • Orgadrone
  • Spersadex
  • Visumetazone

Other: Laboratory Biomarker Analysis
Correlative studies

Drug: Lenalidomide
Given PO
Other Names:
  • CC-5013
  • CC5013
  • CDC 501
  • Revlimid

Other: Pharmacological Study
Correlative studies

Drug: R-(-)-Gossypol Acetic Acid
Given PO
Other Names:
  • (-)-Gossypol Acetic Acid
  • AT-101
  • GOSSYPOL ACETIC ACID, (R)-




Primary Outcome Measures :
  1. Maximally tolerated dose of AT-101 in combination with lenalidomide and dexamethasone defined as the dose level below the lowest dose that induces dose-limiting toxicity in at least one-third of patients (Phase I) [ Time Frame: Up to day 28 of course 2 ]
    The number and severity of all adverse events (overall and by dose-level) will be tabulated and summarized in this patient population. The Grade 3+ adverse events will also be described and summarized in a similar fashion.

  2. Overall response rate, with response defined to be a stringent complete response, complete response, very good partial response, or partial response (Phase II) [ Time Frame: Up to 3 years ]
    Responses will be summarized by simple descriptive summary statistics delineating complete and partial responses as well as stable and progressive disease in this patient population. The proportion of successes will be estimated by the number of successes divided by the total number of evaluable patients. Confidence intervals for the true success proportion will be calculated according to the approach of Duffy and Santner.


Secondary Outcome Measures :
  1. Incidence of adverse events [ Time Frame: Up to 30 days after the last day of study drug treatment ]
    The maximum grade for each type of adverse event, regardless of causality, will be recorded and reported for each patient, and frequency tables will be reviewed to determine adverse event patterns.

  2. Overall survival (Phase II) [ Time Frame: Time from registration to death due to any cause, assessed up to 3 years ]
    Estimated using the method of Kaplan-Meier.

  3. Progression free survival (Phase II) [ Time Frame: Time from registration to the earliest date of documentation of disease progression or death due to any cause, assesse up to 3 years ]
    Estimated using the method of Kaplan-Meier.


Other Outcome Measures:
  1. Biochemical response, measured by change in serum/urine M-proteins and light chains [ Time Frame: Baseline to day 28 of course 1 ]
    The degree of response of these tumor biomarkers will be evaluated (percentage and absolute decrease)

  2. Change in basal expression of Bcl-2 and its family members [ Time Frame: Baseline to after completion of 2 courses of treatment (56 days) ]
    Basal expression will be summarized descriptively for each target. Changes in expression over time will be evaluated for each target using Wilcoxon's signed rank test.

  3. Change in basal expression pattern of protein kinase B (Akt), mitogen-activated protein kinase 1 (Erk), and mitogen-activated protein kinase (MAPK) [ Time Frame: Baseline to after completion of 2 courses of treatment (56 days) ]
    Basal expression will be summarized descriptively for each target. Changes in expression over time will be evaluated for each target using Wilcoxon's signed rank test

  4. Change in Cereblon expression [ Time Frame: Baseline to time of relapse/resistance (relapse after a clinical response or progressive disease while on therapy, up to 3 years) ]
    Analyzed to determine if clinical response to lenalidomide/dexamethasone is linked to Cereblon expression. The expression will be summarized descriptively.

  5. Resistance to AT-101, measured by change in basal Bcl-2 and Mcl-2 binding domain sequence [ Time Frame: Baseline to time of relapse/resistance (up to 3 years) ]
    These targets will be summarized descriptively. The baseline values will be compared with the values at the time of relapse/resistance using Wilcoxon's signed rank test.

  6. Resistance to lenalidomide/dexamethasone, measured by change in expression of signaling molecules Akt, Erk1/2, and MAPK [ Time Frame: Baseline to time of relapse/resistance (up to 3 years) ]
    Comparison will be drawn between the pre-treatment samples and those obtained at time of resistance using Wilcoxon's signed rank test. Correlation will be made with clinical response to therapy (responder vs. non-responder) using Wilcoxon's rank sum test.



Information from the National Library of Medicine

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

Inclusion Criteria:

  • Calculated creatinine clearance (using Cockcroft-Gault equation) >= 60 mL/min
  • Absolute neutrophil count (ANC) >= 1000/mm^3
  • Platelet count >= 75000/mm^3
  • Hemoglobin >= 8.0 g/dL
  • Patient must have relapsed and symptomatic multiple myeloma
  • Measurable disease of multiple myeloma as defined by at least ONE of the following:

    • Serum monoclonal protein >= 1.0 g/dL
    • > 200 mg of monoclonal protein in the urine on 24 hour electrophoresis
    • Serum immunoglobulin free light chain >= 10 mg/dL AND abnormal serum immunoglobulin kappa to lambda free light chain ratio
  • Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1 or 2
  • Patients must have received at least 1 prior regimen
  • Provide informed written consent
  • Negative pregnancy test done =< 7 days prior to registration, for women of childbearing potential only
  • Willing to return to enrolling institution for follow-up (during the active monitoring phase of the study)
  • Willing to provide bone marrow and blood samples for correlative research purposes

Exclusion Criteria:

  • Monoclonal gammopathy of undetermined significance (MGUS) or smoldering myeloma
  • Patients who have received > 3 prior treatment regimens for multiple myeloma
  • Other malignancy requiring active therapy; exceptions: non-melanotic skin cancer or carcinoma-in-situ of the cervix; Note: if there is a history of prior malignancy, they must not be receiving other specific treatment for their cancer
  • Any of the following:

    • Pregnant women
    • Nursing women
    • Men or women of childbearing potential who are unwilling to employ adequate contraception
  • Other co-morbidity which would interfere with patient's ability to participate in trial, e.g. uncontrolled infection, uncompensated heart or lung disease
  • Other concurrent chemotherapy, radiotherapy, or any ancillary therapy considered investigational; Note: bisphosphonates are considered to be supportive care rather than therapy, and are thus allowed while on protocol treatment
  • Prior severe skin reaction (toxic epidermal necrosis) with immunomodulating agents
  • Major surgery =< 14 days before study registration
  • Concurrent medical problems that preclude use of deep vein thrombosis (DVT) prophylaxis with lenalidomide treatment
  • Evidence of current uncontrolled cardiovascular conditions, including cardiac arrhythmias, congestive heart failure, angina, or myocardial infarction =< 6 months prior to registration
  • Known human immunodeficiency virus (HIV) positive
  • Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol
  • Known allergy to any of the study medications, their analogues or excipients in the various formulations

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): NCT02697344


Locations
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United States, Florida
Mayo Clinic in Florida
Jacksonville, Florida, United States, 32224-9980
Sponsors and Collaborators
Mayo Clinic
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Asher Chanan-Khan Mayo Clinic

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Responsible Party: Mayo Clinic
ClinicalTrials.gov Identifier: NCT02697344     History of Changes
Other Study ID Numbers: mc1384
NCI-2016-00073 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
15-003501
mc1384 ( Other Identifier: Mayo Clinic in Florida )
P30CA015083 ( U.S. NIH Grant/Contract )
First Posted: March 3, 2016    Key Record Dates
Last Update Posted: October 31, 2018
Last Verified: October 2018

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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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
Dexamethasone
Dexamethasone acetate
Lenalidomide
Retinol acetate
Gossypol acetic acid
BB 1101
Acetic Acid
Gossypol
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Glucocorticoids
Hormones