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Gossypol Acetic Acid With Lenalidomide and Dexamethasone in Treating Patients With Relapsed Symptomatic Multiple Myeloma

Primary Purpose

Recurrent Plasma Cell Myeloma

Status

Active

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Dexamethasone

Laboratory Biomarker Analysis

Lenalidomide

Pharmacological Study

R-(-)-Gossypol Acetic Acid

About this trial

This is an interventional treatment trial for Recurrent Plasma Cell Myeloma

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Mayo Clinic in Florida

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (AT-101, lenalidomide, and dexamethasone)

Arm Description

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.

Outcomes

Primary Outcome Measures

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)

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.

Overall response rate, with response defined to be a stringent complete response, complete response, very good partial response, or partial response (Phase II)

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

Incidence of adverse events

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.

Overall survival (Phase II)

Estimated using the method of Kaplan-Meier.

Progression free survival (Phase II)

Estimated using the method of Kaplan-Meier.

Full Information

NCT ID

NCT02697344

First Posted

February 22, 2016

Last Updated

July 7, 2023

Sponsor

Mayo Clinic

1. Study Identification

Unique Protocol Identification Number

NCT02697344

Brief Title

Gossypol Acetic Acid With Lenalidomide and Dexamethasone in Treating Patients With Relapsed Symptomatic Multiple Myeloma

Official Title

Phase I/II Trial of AT-101 in Combination With Lenalidomide and Dexamethasone in Patients With Relapsed Symptomatic Multiple Myeloma

Study Type

Interventional

2. Study Status

Record Verification Date

April 2023

Overall Recruitment Status

Active, not recruiting

Study Start Date

April 14, 2016 (Actual)

Primary Completion Date

October 26, 2018 (Actual)

Study Completion Date

December 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Mayo Clinic

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

This phase I 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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Recurrent Plasma Cell Myeloma

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

10 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Treatment (AT-101, lenalidomide, and dexamethasone)

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Dexamethasone

Other Intervention Name(s)

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

Intervention Description

Given PO

Intervention Type

Other

Intervention Name(s)

Laboratory Biomarker Analysis

Intervention Description

Correlative studies

Intervention Type

Drug

Intervention Name(s)

Lenalidomide

Other Intervention Name(s)

CC-5013, CC5013, CDC 501, Revlimid

Intervention Description

Given PO

Intervention Type

Other

Intervention Name(s)

Pharmacological Study

Intervention Description

Correlative studies

Intervention Type

Drug

Intervention Name(s)

R-(-)-Gossypol Acetic Acid

Other Intervention Name(s)

(-)-Gossypol Acetic Acid, AT-101, GOSSYPOL ACETIC ACID, (R)-

Intervention Description

Given PO

Primary Outcome Measure Information:

Title

Description

Time Frame

Up to day 28 of course 2

Title

Overall response rate, with response defined to be a stringent complete response, complete response, very good partial response, or partial response (Phase II)

Description

Time Frame

Up to 3 years

Secondary Outcome Measure Information:

Title

Incidence of adverse events

Description

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.

Time Frame

Up to 30 days after the last day of study drug treatment

Title

Overall survival (Phase II)

Description

Estimated using the method of Kaplan-Meier.

Time Frame

Time from registration to death due to any cause, assessed up to 3 years

Title

Progression free survival (Phase II)

Description

Estimated using the method of Kaplan-Meier.

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

Other Pre-specified Outcome Measures:

Title

Biochemical response, measured by change in serum/urine M-proteins and light chains

Description

The degree of response of these tumor biomarkers will be evaluated (percentage and absolute decrease)

Time Frame

Baseline to day 28 of course 1

Title

Change in basal expression of Bcl-2 and its family members

Description

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.

Time Frame

Baseline to after completion of 2 courses of treatment (56 days)

Title

Change in basal expression pattern of protein kinase B (Akt), mitogen-activated protein kinase 1 (Erk), and mitogen-activated protein kinase (MAPK)

Description

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

Time Frame

Baseline to after completion of 2 courses of treatment (56 days)

Title

Change in Cereblon expression

Description

Analyzed to determine if clinical response to lenalidomide/dexamethasone is linked to Cereblon expression. The expression will be summarized descriptively.

Time Frame

Baseline to time of relapse/resistance (relapse after a clinical response or progressive disease while on therapy, up to 3 years)

Title

Resistance to AT-101, measured by change in basal Bcl-2 and Mcl-2 binding domain sequence

Description

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.

Time Frame

Baseline to time of relapse/resistance (up to 3 years)

Title

Resistance to lenalidomide/dexamethasone, measured by change in expression of signaling molecules Akt, Erk1/2, and MAPK

Description

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.

Time Frame

Baseline to time of relapse/resistance (up to 3 years)

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility 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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Asher Chanan-Khan

Organizational Affiliation

Mayo Clinic

Official's Role

Principal Investigator

Facility Information:

Facility Name

Mayo Clinic in Florida

City

Jacksonville

State/Province

Florida

ZIP/Postal Code

32224-9980

Country

United States

12. IPD Sharing Statement

Links:

URL

https://www.mayo.edu/research/clinical-trials

Description

Mayo Clinic Clinical Trials

Learn more about this trial

Gossypol Acetic Acid With Lenalidomide and Dexamethasone in Treating Patients With Relapsed Symptomatic Multiple Myeloma

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