Sapacitabine, Cyclophosphamide, Rituximab for Relapsed Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma (CLL/SLL) With Deletion (11q22-23)

• Sponsor: M.D. Anderson Cancer Center (Other)
• Overall Status: Terminated
• CT.gov ID: NCT01253460
• Collaborator: Cyclacel Pharmaceuticals, Inc. (Industry), National Cancer Institute (NCI) (NIH)
• Enrollment: 18
• Location: 1
• Arm: 1
• Actual Duration (Months): 89.8
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The goal of this clinical research study is to learn if sapacitabine given in combination with 2 standard drugs (cyclophosphamide and rituximab) can help to control CLL and SLL. The safety of this drug combination will also be studied.

Condition or Disease	Intervention/Treatment	Phase
Leukemia	Drug: Cyclophosphamide; Drug: Rituximab; Drug: Sapacitabine	Phase 2

Detailed Description

The Study Drugs:

Sapacitabine and cyclophosphamide are designed to damage the DNA (genetic material) of cancer cells, which may cause the cancer cells to die.

Rituximab is designed to attach to cancer cells and damage them, which may cause the cancer cells to die. It is also designed to cause the immune system to attack cancer cells.

Study Drug Administration:

If you are found to be eligible to take part in this study, you will receive sapacitabine by mouth 1 time a day on Days 1-3 of each 28-day cycle. Try to take sapacitabine at least 1 hour before or 2 hours after a meal. On Days 1-3 of each cycle, you will also receive cyclophosphamide by vein over 30 minutes, starting 2 hours after you take sapacitabine.

On Day 3 of Cycle 1 and Day 1 of Cycles 2 and beyond, you will receive rituximab by vein over 6-8 hours.

If side effects occur, the study doctor may decide to lower your study drug doses. If you have side effects during a dose, the study staff will check you for any other problems for 2 hours after the dose.

Other Drugs:

On Days 1-14 of Cycle 1, you will take allopurinol by mouth 1 time a day to lower the risk of kidney damage.

Before each dose of cyclophosphamide, you will receive Zofran (ondansetron) by vein over a few seconds to lower the risk of nausea.

About 30-60 minutes before each dose of rituximab, you will take Tylenol (acetaminophen) and Benadryl (diphenhydramine hydrochloride) by mouth to lower the risk of side effects such as fever and chills.

Study Visits:

On Day 1 of each cycle:

• Blood (about 1-2 tablespoons) will be drawn for routine tests.

• You will also have a physical exam, including measurement of your vital signs, except Cycle 1.

• You will be asked about any side effects you may have had.

On Days 8 and 22 of Cycle 1, and on Day 15 of every cycle:

• Blood (about 1-2 tablespoons) will be drawn for routine tests.

• You will be asked about any side effects you may have had.

If your disease has had a good response and the doctor thinks it is needed to check the status of the disease, you will have a bone marrow aspiration and biopsy and a CT scan of the chest, abdomen and pelvis prior to Cycle 4 and possibly every other cycle after that (Cycles 6, 8, 10, and so on).

Length of Study:

Once your doctor thinks the disease has had its best response, you may receive 2 more cycles of study therapy after that. You will no longer be able to receive the study drugs if the disease gets worse or intolerable side effects occur.

End-of-Treatment Visit:

The following tests and procedures will be performed after your last cycle of study drugs:

• You will have a physical exam, including measurement of your vital signs.

• Blood (about 2 tablespoons) will be drawn for routine tests.

Follow-Up Visits:

At 2 and 6 months and 1 and 2 years after your last dose of study drugs:

• You will be asked about any side effects you may have had and any drugs you may be taking.

• You will have a physical exam, including measurement of your vital signs.

• Blood (about 1 tablespoon) will be drawn for routine tests.

• If the doctor thinks the disease has completely responded, you will have a CT scan of the neck, chest, abdomen, and pelvis to confirm the response. You will also have a bone marrow aspiration and biopsy to confirm the response.

At 3 years after your last dose of study drugs and 1 time a year from then on:

• You will be asked about any side effects you may have had and any drugs you may be taking.

• You will have a physical exam, including measurement of your vital signs.

• Blood (about 1 tablespoon) will be drawn for routine tests.

• You will have a bone marrow aspiration and biopsy if the doctor decides it is needed to check the status of the disease.

If the doctor thinks it is needed anytime during follow-up, you will have a CT scan of the neck, chest, abdomen, and pelvis to check the status of the disease.

Starting at Year 3, the follow-up tests and procedures can be done by your local doctor if that is more convenient to you. The test results should be sent to MD Anderson.

You should tell your study doctor or staff if you start another cancer treatment during follow-up. If that occurs, your follow-up in this study will stop.

This is an investigational study. Sapacitabine is not FDA approved or commercially available. It is currently being used for research purposes only. Cyclophosphamide and rituximab are FDA approved and commercially available to treat CLL and SLL. The combination of sapacitabine, cyclophosphamide, and rituximab is investigational.

Up to 40 patients will take part in this study. All will be enrolled at MD Anderson.

Study Design

• Study Type: Interventional
• Actual Enrollment: 18 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Clinical Trial of Sapacitabine, Cyclophosphamide, and Rituximab (SCR) for Relapsed Patients With Chronic Lymphocytic Leukemia / Small Lymphocytic Lymphoma (CLL/SLL) and Deletion 11q22-23 by FISH
• Actual Study Start Date: Aug 22, 2011
• Actual Primary Completion Date: Mar 28, 2018
• Actual Study Completion Date: Feb 13, 2019

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Cyclophosphamide, Rituximab + Sapacitabine After Sapacitabine 350 mg orally Days 1-3, Cyclophosphamide 250 mg/m2 IV 2 hours, followed by Rituximab 375 mg/m2 IV Day 3, Course 1, and 500 mg/m2 Day 1, subsequent courses.

Drug: Cyclophosphamide; 250 mg/m2 by vein (IV) over 30 minutes, 2 hours following the dose of Sapacitabine on days 1, 2, and 3 of each 28 day course.; Other Names: Cytoxan Neosar ; Drug: Rituximab; 375 mg/m2 by vein over 6 - 8 hours on day 3 of course 1 after cyclophosphamide, then at 500 mg/m2 on day 1, after cyclophosphamide for subsequent courses. Each course is 28 days.; Other Names: Rituxan ; Drug: Sapacitabine; 350 mg flat dose by mouth in the morning of days 1,2, and 3 of each 28 day course.

Outcome Measures

Primary Outcome Measures

1. Overall Response Rate (ORR) [84 days]

   Patients evaluated for response by 2008 International Workshop on Chronic Lymphocytic Leukemia [IWCLL] overall response criteria before course 4, then after every 2 courses, and at end of treatment (2 months after last course). Overall Response Rate (ORR) = Complete Response (CR) + Partial Response (PR). Complete response is the absence of signs and symptoms, normalization of peripheral blood and bone marrow and lymph nodes 1.5 cm in diameter or smaller on CT scan. Partial response is at least 50% reduction in disease signs and symptoms, a 50% improvement in peripheral blood and greater than or equal to 50% reduction in lymph nodes.

Secondary Outcome Measures

1. Overall Survival [Up to 8.5 years]

   Time from date of treatment start until date of death due to any cause or last Follow-up.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

1. Patients must have a diagnosis of CLL/SLL and be previously treated

2. Patients must have had Fluorescence in situ Hybridization (FISH) evaluation of leukemia cells within 3 months without intervening treatment demonstrating deletion 11q22-23

3. Patients must have an indication for treatment by 2008 International Workshop on Chronic Lymphocytic Leukemia (IWCLL) Criteria

4. Age >/= 18 years

5. Eastern Cooperative Oncology Group (ECOG)/Zubrod performance status </= 2

6. Adequate renal and hepatic function as indicated by all the following: serum creatinine </= 2 mg/dL AND; alanine aminotransferase (ALT) </= 2.5 times upper limit of normal; AND total bilirubin </= 2.5 times upper limit of normal

7. Patients must have an Absolute neutrophil count (ANC) >/= 500/uL, Hemoglobin (HGB) >/= 8 gm/dL, Platelets (PLT) count >/= 20K/uL, unless attributed to marrow infiltration with CLL

8. Patients must give written informed consent

9. Patients of childbearing potential (females who have not been postmenopausal for at least 12 consecutive months or who have not undergone previous surgical sterilization or males who have not been surgically sterilized) must be willing to practice birth control during the study

Exclusion Criteria:

1. Pregnant or breast-feeding females

2. Significant co-morbidity indicated by major organ system dysfunction

3. Active infection, uncontrolled with intravenous antibiotics

4. Uncontrolled autoimmune hemolytic anemia (AIHA) or immune thrombocytopenia purpura (ITP)

5. Treatment including chemotherapy, chemoimmunotherapy, monoclonal antibody therapy, radiotherapy, high-dose corticosteroid therapy (prednisone >/= 60 mg daily, or equivalent), or immunotherapy within 3 weeks prior to enrollment or concurrent with this trial

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Texas MD Anderson Cancer Center	Houston	Texas	United States	77030

Sponsors and Collaborators

• M.D. Anderson Cancer Center
• Cyclacel Pharmaceuticals, Inc.
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: William G. Wierda, MD, PHD, BS, M.D. Anderson Cancer Center

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jun 28, 2012

More Information

Additional Information:

• University of Texas MD Anderson Cancer Center Website

Publications

None provided.

• Responsible Party: M.D. Anderson Cancer Center
• ClinicalTrials.gov Identifier: NCT01253460
• Other Study ID Numbers: 2010-0516; NCI-2011-00119; 5P01CA081534
• First Posted: Dec 3, 2010
• Last Update Posted: Sep 6, 2019
• Last Verified: Aug 1, 2019

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by M.D. Anderson Cancer Center: Chronic Lymphocytic Leukemia; CLL; Small Lymphocytic Lymphoma; SLL; Cyclophosphamide; Rituximab; Sapacitabine; Cytoxan; Neosar; Rituxan
• Additional relevant MeSH terms: Lymphoma; Leukemia; Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell; Cyclophosphamide; Rituximab; Sapacitabine

Study Results

Participant Flow

Recruitment Details	Recruitment Period: 8/22/2011 to 12/19/2013

Arm/Group Title	Cyclophosphamide, Rituximab + Sapacitabine
Arm/Group Description	After Sapacitabine 350 mg orally Days 1-3, Cyclophosphamide 250 mg/m2 IV 2 hours, followed by Rituximab 375 mg/m2 IV Day 3, Course 1, and 500 mg/m2 Day 1, subsequent courses. Cyclophosphamide: 250 mg/m2 by vein (IV) over 30 minutes, 2 hours following the dose of Sapacitabine on days 1, 2, and 3 of each 28 day course. Rituximab: 375 mg/m2 by vein over 6 - 8 hours on day 3 of course 1 after cyclophosphamide, then at 500 mg/m2 on day 1, after cyclophosphamide for subsequent courses. Each course is 28 days. Sapacitabine: 350 mg flat dose by mouth in the morning of days 1,2, and 3 of each 28 day course.
Period Title: Overall Study
STARTED	18
COMPLETED	18
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Cyclophosphamide, Rituximab + Sapacitabine
Arm/Group Description	After Sapacitabine 350 mg orally Days 1-3, Cyclophosphamide 250 mg/m2 IV 2 hours, followed by Rituximab 375 mg/m2 IV Day 3, Course 1, and 500 mg/m2 Day 1, subsequent courses. Cyclophosphamide: 250 mg/m2 by vein (IV) over 30 minutes, 2 hours following the dose of Sapacitabine on days 1, 2, and 3 of each 28 day course. Rituximab: 375 mg/m2 by vein over 6 - 8 hours on day 3 of course 1 after cyclophosphamide, then at 500 mg/m2 on day 1, after cyclophosphamide for subsequent courses. Each course is 28 days. Sapacitabine: 350 mg flat dose by mouth in the morning of days 1,2, and 3 of each 28 day course.
Overall Participants	18
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	8 44.4%
>=65 years	10 55.6%
Sex: Female, Male (Count of Participants)
Female	3 16.7%
Male	15 83.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	18 100%
Unknown or Not Reported	0 0%
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	3 16.7%
White	15 83.3%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	18 100%

Outcome Measures

1. Primary Outcome

Title	Overall Response Rate (ORR)
Description	Patients evaluated for response by 2008 International Workshop on Chronic Lymphocytic Leukemia [IWCLL] overall response criteria before course 4, then after every 2 courses, and at end of treatment (2 months after last course). Overall Response Rate (ORR) = Complete Response (CR) + Partial Response (PR). Complete response is the absence of signs and symptoms, normalization of peripheral blood and bone marrow and lymph nodes 1.5 cm in diameter or smaller on CT scan. Partial response is at least 50% reduction in disease signs and symptoms, a 50% improvement in peripheral blood and greater than or equal to 50% reduction in lymph nodes.
Time Frame	84 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cyclophosphamide, Rituximab + Sapacitabine
Arm/Group Description	After Sapacitabine 350 mg orally Days 1-3, Cyclophosphamide 250 mg/m2 IV 2 hours, followed by Rituximab 375 mg/m2 IV Day 3, Course 1, and 500 mg/m2 Day 1, subsequent courses. Cyclophosphamide: 250 mg/m2 by vein (IV) over 30 minutes, 2 hours following the dose of Sapacitabine on days 1, 2, and 3 of each 28 day course. Rituximab: 375 mg/m2 by vein over 6 - 8 hours on day 3 of course 1 after cyclophosphamide, then at 500 mg/m2 on day 1, after cyclophosphamide for subsequent courses. Each course is 28 days. Sapacitabine: 350 mg flat dose by mouth in the morning of days 1,2, and 3 of each 28 day course.
Measure Participants	18
Count of Participants [Participants]	8 44.4%

2. Secondary Outcome

Title	Overall Survival
Description	Time from date of treatment start until date of death due to any cause or last Follow-up.
Time Frame	Up to 8.5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cyclophosphamide, Rituximab + Sapacitabine
Arm/Group Description	After Sapacitabine 350 mg orally Days 1-3, Cyclophosphamide 250 mg/m2 IV 2 hours, followed by Rituximab 375 mg/m2 IV Day 3, Course 1, and 500 mg/m2 Day 1, subsequent courses. Cyclophosphamide: 250 mg/m2 by vein (IV) over 30 minutes, 2 hours following the dose of Sapacitabine on days 1, 2, and 3 of each 28 day course. Rituximab: 375 mg/m2 by vein over 6 - 8 hours on day 3 of course 1 after cyclophosphamide, then at 500 mg/m2 on day 1, after cyclophosphamide for subsequent courses. Each course is 28 days. Sapacitabine: 350 mg flat dose by mouth in the morning of days 1,2, and 3 of each 28 day course.
Measure Participants	18
Median (Full Range) [Months]	31

Adverse Events

Time Frame	Up to 8.5 years
Arm/Group Title	Cyclophosphamide, Rituximab + Sapacitabine
Arm/Group Description	After Sapacitabine 350 mg orally Days 1-3, Cyclophosphamide 250 mg/m2 IV 2 hours, followed by Rituximab 375 mg/m2 IV Day 3, Course 1, and 500 mg/m2 Day 1, subsequent courses. Cyclophosphamide: 250 mg/m2 by vein (IV) over 30 minutes, 2 hours following the dose of Sapacitabine on days 1, 2, and 3 of each 28 day course. Rituximab: 375 mg/m2 by vein over 6 - 8 hours on day 3 of course 1 after cyclophosphamide, then at 500 mg/m2 on day 1, after cyclophosphamide for subsequent courses. Each course is 28 days. Sapacitabine: 350 mg flat dose by mouth in the morning of days 1,2, and 3 of each 28 day course.
All Cause Mortality
	Cyclophosphamide, Rituximab + Sapacitabine
	Affected / at Risk (%)	# Events
Total	2/18 (11.1%)
Serious Adverse Events
	Cyclophosphamide, Rituximab + Sapacitabine
	Affected / at Risk (%)	# Events
Total	7/18 (38.9%)
Cardiac disorders
Atrial Fibrillation	1/18 (5.6%)	1
Gastrointestinal disorders
Anorexia	1/18 (5.6%)	1
General disorders
Lymph node pain	1/18 (5.6%)	1
Infections and infestations
Neutropenic Fever	1/18 (5.6%)	1
Sepsis	1/18 (5.6%)	1
Soft Tissue Infection	1/18 (5.6%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Leukemia Secondary to Chemotherapy	2/18 (11.1%)	2
Neoplasms benign	1/18 (5.6%)	1
Nervous system disorders
Sycnope	1/18 (5.6%)	1
Renal and urinary disorders
Acute Kidney Injury	1/18 (5.6%)	1
Renal Calculi	1/18 (5.6%)	1
Respiratory, thoracic and mediastinal disorders
Dyspena	1/18 (5.6%)	1
Respiratory Failure	1/18 (5.6%)	1
Other (Not Including Serious) Adverse Events
	Cyclophosphamide, Rituximab + Sapacitabine
	Affected / at Risk (%)	# Events
Total	18/18 (100%)
Blood and lymphatic system disorders
Anemia	4/18 (22.2%)	17
Neutropenia	12/18 (66.7%)	48
Thrombocytopenia	8/18 (44.4%)	33
Edema, Limbs	4/18 (22.2%)	4
Epistaxis	3/18 (16.7%)	3
Cardiac disorders
Atrial Fibrillation	1/18 (5.6%)	1
Endocrine disorders
Hot Flashes	5/18 (27.8%)	5
Gastrointestinal disorders
Abdominal Distension	3/18 (16.7%)	3
Anorexia	3/18 (16.7%)	3
Constipation	3/18 (16.7%)	3
Dehydration	2/18 (11.1%)	2
Diarrhea	5/18 (27.8%)	5
Dyspepsia	2/18 (11.1%)	2
Nausea	7/18 (38.9%)	7
Vomiting	2/18 (11.1%)	2
General disorders
Chills	5/18 (27.8%)	5
Fatigue	1/18 (5.6%)	1
Fever	4/18 (22.2%)	4
Headache	2/18 (11.1%)	2
Pain, Extremity	2/18 (11.1%)	2
Infections and infestations
Infection	1/18 (5.6%)	1
Investigations
Infusion Reaction	2/18 (11.1%)	2
Metabolism and nutrition disorders
Hypomagnesemia	1/18 (5.6%)	1
Hyperglycemia	3/18 (16.7%)	3
Hypernatremia	1/18 (5.6%)	1
Hypocalcemia	2/18 (11.1%)	2
Elevated Creatinine	4/18 (22.2%)	4
Hyperkalemia	2/18 (11.1%)	2
Hyperuricemia	3/18 (16.7%)	3
Hyperbilirubinemia	1/18 (5.6%)	1
Musculoskeletal and connective tissue disorders
Pain, arthralgia	3/18 (16.7%)	3
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Squamous Cell Carcinoma	1/18 (5.6%)	1
Nervous system disorders
Dizziness	2/18 (11.1%)	2
Respiratory, thoracic and mediastinal disorders
Dyspnea	3/18 (16.7%)	3

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.