Lenalidomide and AT-101 in Treating Patients With Relapsed B-Cell Chronic Lymphocytic Leukemia

• Sponsor: Mayo Clinic (Other)
• Overall Status: Terminated
• CT.gov ID: NCT01003769
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 5
• Locations: 2
• Arm: 1
• Actual Duration (Months): 41.2
• Patients Per Site: 2.5
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This phase I/II trial studies the side effects and best dose of lenalidomide when given together with R-(-)-gossypol acetic acid and to see how well they work in treating patients with B-cell chronic lymphocytic leukemia (B-CLL) that has returned after a period of improvement (relapsed). Biological therapies, such as lenalidomide, may stimulate the immune system to attack cancer cells. R-(-)-gossypol acetic acid may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth and causing the cells to die. Giving lenalidomide with R-(-)-gossypol acetic acid may be an effective treatment for relapsed or refractory B-CLL. - Funding Source - FDA OOPD

Condition or Disease	Intervention/Treatment	Phase
Recurrent Chronic Lymphocytic Leukemia	Drug: Lenalidomide; Drug: R-(-)-Gossypol Acetic Acid; Other: Laboratory Biomarker Analysis	Phase 1/Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. To determine the maximum tolerated dose (MTD) of lenalidomide in combination with AT-101 (R-(-)-gossypol acetic acid). (Phase I) II. To assess the overall response rate of lenalidomide in combination with AT-101. (Phase II)

SECONDARY OBJECTIVES:

1. To assess the overall response rates of lenalidomide in combination with AT-101 at 6 months and 12 months.

2. To evaluate time to progression (TTP) for the combination of lenalidomide + AT-101.

3. To evaluate the safety of this combination in patients with relapsed B-CLL.

TERTIARY OBJECTIVES:

1. To conduct correlative studies for further understanding of the mechanism of antitumor activity of lenalidomide and lenalidomide + AT-101.

OUTLINE: This is a phase I dose-escalation study of lenalidomide followed by a phase II study.

Patients receive lenalidomide orally (PO) once daily (QD) on days 1-21. Beginning in course 3, patients also receive AT-101 PO twice daily (BID) on days 1-3. Treatment repeats every 28 days for up to 11 courses (49-56 days for course 12 or last course of treatment) in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days and then every 3 months for up to 2 years.

Study Design

• Study Type: Interventional
• Actual Enrollment: 5 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I/II Clinical Trial of Lenalidomide in Combination With AT-101 for the Treatment of Relapsed B-Cell Chronic Lymphocytic Leukemia (B-CLL)
• Actual Study Start Date: Jul 9, 2015
• Actual Primary Completion Date: Dec 14, 2018
• Actual Study Completion Date: Dec 14, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (lenalidomide in combination with AT-101) Patients receive lenalidomide PO QD on days 1-21. Beginning in course 2, patients also receive AT-101 PO BID on days 1-3. Treatment repeats every 28 days for up to 11 courses (49-56 days for course 12 or last course of treatment) in the absence of disease progression or unacceptable toxicity.	Drug: Lenalidomide; Given PO; Other Names: CC-5013 CC5013 CDC 501 IMiD-1 ; Drug: R-(-)-Gossypol Acetic Acid; Given PO; Other Names: (-)-Gossypol Acetic Acid AT-101 ; Other: Laboratory Biomarker Analysis; Correlative studies

Outcome Measures

Primary Outcome Measures

1. Maximum Tolerated Dose [Up to day 28 of course 2]

   Maximum tolerated dose of lenalidomide when given in combination with AT-101, defined as the dose level below the lowest dose that induces dose limiting toxicity in at least one-third of patients (at least 2 of a maximum of 6 new patients) (Phase I)

2. Overall Response Rate (Complete Response [CR], CR With Incomplete Marrow Recovery, Clinical CR, Nodular Partial Response [PR], and PR) (Phase II) [Up to 2 years]

   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, Graded According to the Grading Scale for Hematologic Adverse Events in CLL Studies (Phase I) [Up to 2 years]

   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. Incidence of Toxicity, Defined as Adverse Events Classified as Possibly, Probably, or Definitely Related to Study Treatment, Graded According to the Grading Scale for Hematologic Adverse Events in CLL Studies or Ordinal Common Toxicity Criteria (Phase I) [Up to 2 years]

   Overall toxicity incidence as well as toxicity profiles by dose level, patient and tumor site will be explored and summarized. Frequency distributions, graphical techniques and other descriptive measures will form the basis of these analyses. Here, we report the number of patients that reported a grade 2 or higher as their worst incidence of toxicity.

3. Overall Response Rate (Phase II) [Up to 12 months]

   The proportion of responses by 6 months will be estimated by the number of patients who achieve a response by 6 months divided by the total number of evaluable patients. The proportion of responses by 12 months will be estimated in a similar manner. Exact binomial 95% confidence intervals for the true success proportions will be calculated.

4. Time to Progression (Phase II) [The time from registration to the earliest date of documentation of disease progression, assessed up to 2 years]

   The distribution of time to progression will be estimated using the method of Kaplan-Meier.

5. Incidence of Adverse Events, Graded According to the Grading Scale for Hematologic Adverse Events in CLL Studies (Phase II) [Up to 30 days after the last day of study 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Understand and voluntarily sign an informed consent form

• Able to adhere to the study visit schedule and other protocol requirements

• Diagnosis of B-CLL, confirmed by flow cytometric analysis and as per the criteria outlined by the International Workshop on Chronic Lymphocytic Leukemia (IWCLL)/Hallek December 2008

• Any prior therapy for B-CLL must have been discontinued >= 28-days prior to registration

• Patients must have absolute lymphocyte counts (ALC) of more than 5,000 cell/mm^3

• During phase I: all patients with relapsed disease will be eligible if they have received at least 1 prior standard CLL therapy and no more than 4 prior therapies (one of which must be a purine analog and/or an alkylating agent)

• During phase II: all patients with relapsed disease will be eligible if they have received a minimum of 1 prior standard therapy and a maximum of 2 prior treatments (one of which must be a purine analog and/or an alkylating agent) for B-CLL and have developed relapse disease

• Note: patients who have refractory disease (defined as - progressive disease on last treatment, or less than 6 months of clinical response to the last treatment) will not be eligible

• Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 at registration

• Absolute neutrophil count >= 1500/mm^3

• Platelet count >= 30,000/mm^3

• Serum creatinine =< 1.5 x upper limit of normal (ULN)

• Total bilirubin =< 1.5 mg/dL or direct bilirubin =< 1.0 mg/dL for patients with Gilberts syndrome

• Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) and serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 2 x ULN or =< 5 x ULN if hepatic disease is present

• Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL 10-14 days prior to and again within 24 hours before starting lenalidomide and must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME, at least 28 days before she starts taking lenalidomide; FCBP must also agree to ongoing pregnancy testing; men must agree to use a latex condom during sexual contact with a FCBP even if they have had a successful vasectomy; all patients must be counseled at a minimum of every 28 days about pregnancy precautions and risks of fetal exposure

• A female of childbearing potential is a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)

• All study participants must be registered into the mandatory RevAssist program, and be willing and able to comply with the requirements of RevAssist

• Patient must require treatment for symptomatic B-CLL as defined by the by the IWCLL/Hallek, December 2008 criterion or as determined clinically necessary by the treating physician

• Willing to provide blood and baseline bone marrow aspirate samples for correlative research purposes

Exclusion Criteria:

• Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from signing the informed consent form

• Pregnant or lactating females

• Any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study

• Use of any other experimental drug or therapy =< 28 days prior to registration

• Known hypersensitivity to thalidomide or lenalidomide

• The development of erythema nodosum if characterized by a desquamating rash while taking thalidomide or similar drugs

• Patients with of history of any other cancer (except nonmelanoma skin cancer or carcinoma in-situ of the cervix, unless in complete remission and off therapy for that disease for > 3 years)

• Patient with history of cardiac arrest within the past 6 months

• Patients with history of prior bowel resection, malabsorption syndrome, inflammatory bowel disease, prior bowel obstruction (partial or complete), Crohn disease, or any other disease significantly affecting the gastrointestinal tract

• Prior use of gossypol or AT-101

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic in Florida	Jacksonville	Florida	United States	32224-9980
2	Roswell Park Cancer Institute	Buffalo	New York	United States	14263

Sponsors and Collaborators

• Mayo Clinic
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Asher Chanan-Khan, Mayo Clinic

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Feb 5, 2015

More Information

Publications

None provided.

• Responsible Party: Mayo Clinic
• ClinicalTrials.gov Identifier: NCT01003769
• Other Study ID Numbers: MC128A; NCI-2009-01569; MC128A; P30CA015083; 3938; NCT01021345
• First Posted: Oct 29, 2009
• Last Update Posted: Jun 16, 2020
• Last Verified: Jun 1, 2020

• Additional relevant MeSH terms: Leukemia; Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell; Acetic Acid; Lenalidomide; Retinol acetate; Gossypol acetic acid; Gossypol

Study Results

Participant Flow

Arm/Group Title	Dose Level 1 (Lenalidomide in Combination With AT-101)
Arm/Group Description	Patients receive 5 mg lenalidomide PO QD on days 1-21. Beginning in course 2, patients also receive 40 mg AT-101 PO BID on days 1-3. Treatment repeats every 28 days for up to 11 courses (49-56 days for course 12 or last course of treatment) in the absence of disease progression or unacceptable toxicity.
Period Title: Overall Study
STARTED	5
COMPLETED	5
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Dose Level 1 (Lenalidomide in Combination With AT-101)
Arm/Group Description	Patients receive 5 mg lenalidomide PO QD on days 1-21. Beginning in course 2, patients also receive 40 mg AT-101 PO BID on days 1-3. Treatment repeats every 28 days for up to 11 courses (49-56 days for course 12 or last course of treatment) in the absence of disease progression or unacceptable toxicity.
Overall Participants	5
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	61
Sex: Female, Male (Count of Participants)
Female	1 20%
Male	4 80%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	4 80%
Unknown or Not Reported	1 20%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	5 100%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	5 100%

Outcome Measures

1. Primary Outcome

Title	Maximum Tolerated Dose
Description	Maximum tolerated dose of lenalidomide when given in combination with AT-101, defined as the dose level below the lowest dose that induces dose limiting toxicity in at least one-third of patients (at least 2 of a maximum of 6 new patients) (Phase I)
Time Frame	Up to day 28 of course 2

Outcome Measure Data

Analysis Population Description

Trial terminated early with too few patients to analyze this endpoint.

Arm/Group Title	Dose Level 1 (Lenalidomide in Combination With AT-101)
Arm/Group Description	Patients receive 5 mg lenalidomide PO QD on days 1-21. Beginning in course 2, patients also receive 40 mg AT-101 PO BID on days 1-3. Treatment repeats every 28 days for up to 11 courses (49-56 days for course 12 or last course of treatment) in the absence of disease progression or unacceptable toxicity.
Measure Participants	0

2. Primary Outcome

Title	Overall Response Rate (Complete Response [CR], CR With Incomplete Marrow Recovery, Clinical CR, Nodular Partial Response [PR], and PR) (Phase II)
Description	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.
Time Frame	Up to 2 years

Outcome Measure Data

Analysis Population Description

Trial terminated early with too few patients to analyze this endpoint.

Arm/Group Title	Dose Level 1 (Lenalidomide in Combination With AT-101)
Arm/Group Description	Patients receive 5 mg lenalidomide PO QD on days 1-21. Beginning in course 2, patients also receive 40 mg AT-101 PO BID on days 1-3. Treatment repeats every 28 days for up to 11 courses (49-56 days for course 12 or last course of treatment) in the absence of disease progression or unacceptable toxicity.
Measure Participants	0

3. Secondary Outcome

Title	Incidence of Adverse Events, Graded According to the Grading Scale for Hematologic Adverse Events in CLL Studies (Phase I)
Description	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.
Time Frame	Up to 2 years

Outcome Measure Data

Analysis Population Description

Trial terminated early with too few patients to analyze this endpoint.

Arm/Group Title	Dose Level 1 (Lenalidomide in Combination With AT-101)
Arm/Group Description	Patients receive 5 mg lenalidomide PO QD on days 1-21. Beginning in course 2, patients also receive 40 mg AT-101 PO BID on days 1-3. Treatment repeats every 28 days for up to 11 courses (49-56 days for course 12 or last course of treatment) in the absence of disease progression or unacceptable toxicity.
Measure Participants	0

4. Secondary Outcome

Title	Incidence of Toxicity, Defined as Adverse Events Classified as Possibly, Probably, or Definitely Related to Study Treatment, Graded According to the Grading Scale for Hematologic Adverse Events in CLL Studies or Ordinal Common Toxicity Criteria (Phase I)
Description	Overall toxicity incidence as well as toxicity profiles by dose level, patient and tumor site will be explored and summarized. Frequency distributions, graphical techniques and other descriptive measures will form the basis of these analyses. Here, we report the number of patients that reported a grade 2 or higher as their worst incidence of toxicity.
Time Frame	Up to 2 years

Outcome Measure Data

Analysis Population Description

All patients that were registered and treated at dose level 1 are included in this analysis.

Arm/Group Title	Dose Level 1 (Lenalidomide in Combination With AT-101)
Arm/Group Description	Patients receive 5 mg lenalidomide PO QD on days 1-21. Beginning in course 2, patients also receive 40 mg AT-101 PO BID on days 1-3. Treatment repeats every 28 days for up to 11 courses (49-56 days for course 12 or last course of treatment) in the absence of disease progression or unacceptable toxicity.
Measure Participants	5
Grade 2+	1 20%
Grade 3+	4 80%
Grade 4+	0 0%

5. Secondary Outcome

Title	Overall Response Rate (Phase II)
Description	The proportion of responses by 6 months will be estimated by the number of patients who achieve a response by 6 months divided by the total number of evaluable patients. The proportion of responses by 12 months will be estimated in a similar manner. Exact binomial 95% confidence intervals for the true success proportions will be calculated.
Time Frame	Up to 12 months

Outcome Measure Data

Analysis Population Description

Trial terminated early with too few patients to analyze this endpoint.

Arm/Group Title	Dose Level 1 (Lenalidomide in Combination With AT-101)
Arm/Group Description	Patients receive 5 mg lenalidomide PO QD on days 1-21. Beginning in course 2, patients also receive 40 mg AT-101 PO BID on days 1-3. Treatment repeats every 28 days for up to 11 courses (49-56 days for course 12 or last course of treatment) in the absence of disease progression or unacceptable toxicity.
Measure Participants	0

6. Secondary Outcome

Title	Time to Progression (Phase II)
Description	The distribution of time to progression will be estimated using the method of Kaplan-Meier.
Time Frame	The time from registration to the earliest date of documentation of disease progression, assessed up to 2 years

Outcome Measure Data

Analysis Population Description

Trial terminated early with too few patients to analyze this endpoint.

Arm/Group Title	Dose Level 1 (Lenalidomide in Combination With AT-101)
Arm/Group Description	Patients receive 5 mg lenalidomide PO QD on days 1-21. Beginning in course 2, patients also receive 40 mg AT-101 PO BID on days 1-3. Treatment repeats every 28 days for up to 11 courses (49-56 days for course 12 or last course of treatment) in the absence of disease progression or unacceptable toxicity.
Measure Participants	0

7. Secondary Outcome

Title	Incidence of Adverse Events, Graded According to the Grading Scale for Hematologic Adverse Events in CLL Studies (Phase II)
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 treatment

Outcome Measure Data

Analysis Population Description

Trial terminated early with too few patients to analyze this endpoint.

Arm/Group Title	Dose Level 1 (Lenalidomide in Combination With AT-101)
Arm/Group Description	Patients receive 5 mg lenalidomide PO QD on days 1-21. Beginning in course 2, patients also receive 40 mg AT-101 PO BID on days 1-3. Treatment repeats every 28 days for up to 11 courses (49-56 days for course 12 or last course of treatment) in the absence of disease progression or unacceptable toxicity.
Measure Participants	0

Adverse Events

Time Frame	Adverse Events were collected after each 28 day cycle of treatment for up to 4 cycles.
Adverse Event Reporting Description	Adverse Events were collected after each 28 day cycle of treatment for up to 4 cycles.
Arm/Group Title	Dose Level 1 (Lenalidomide in Combination With AT-101)
Arm/Group Description	Patients receive 5 mg lenalidomide PO QD on days 1-21. Beginning in course 2, patients also receive 40 mg AT-101 PO BID on days 1-3. Treatment repeats every 28 days for up to 11 courses (49-56 days for course 12 or last course of treatment) in the absence of disease progression or unacceptable toxicity.
All Cause Mortality
	Dose Level 1 (Lenalidomide in Combination With AT-101)
	Affected / at Risk (%)	# Events
Total	0/5 (0%)
Serious Adverse Events
	Dose Level 1 (Lenalidomide in Combination With AT-101)
	Affected / at Risk (%)	# Events
Total	2/5 (40%)
General disorders
Fatigue	1/5 (20%)	1
Infections and infestations
Lung infection	1/5 (20%)	1
Skin and subcutaneous tissue disorders
Rash maculo-papular	1/5 (20%)	1
Other (Not Including Serious) Adverse Events
	Dose Level 1 (Lenalidomide in Combination With AT-101)
	Affected / at Risk (%)	# Events
Total	5/5 (100%)
Blood and lymphatic system disorders
Anemia	5/5 (100%)	13
Gastrointestinal disorders
Constipation	3/5 (60%)	4
General disorders
Fatigue	1/5 (20%)	1
Infections and infestations
Upper respiratory infection	1/5 (20%)	1
Investigations
Alanine aminotransferase increased	1/5 (20%)	1
Aspartate aminotransferase increased	1/5 (20%)	1
Blood bilirubin increased	1/5 (20%)	1
Neutrophil count decreased	5/5 (100%)	9
Platelet count decreased	5/5 (100%)	12
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumor pain	1/5 (20%)	1
Respiratory, thoracic and mediastinal disorders
Cough	1/5 (20%)	1
Skin and subcutaneous tissue disorders
Pruritus	1/5 (20%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.