CC-4047 in Treating Patients With Myelofibrosis

• Sponsor: Mayo Clinic (Other)
• Overall Status: Completed
• CT.gov ID: NCT00669578
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 77
• Location: 1
• Arm: 1
• Actual Duration (Months): 139.4
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

RATIONALE: Biological therapies, such as CC-4047, may stimulate the immune system in different ways and stop cancer cells from growing. CC-4047 may also stop the growth of cancer cells by blocking blood flow to the cancer.

PURPOSE: This trial is studying the side effects and best dose of CC-4047 and to see how well it works in treating patients with myelofibrosis.

Condition or Disease	Intervention/Treatment	Phase
Chronic Myeloproliferative Disorders; Secondary Myelofibrosis	Drug: CC-4047	Phase 1/Phase 2

Detailed Description

OBJECTIVES:

Phase I:

Primary

• To determine the Maximum Tolerated Dose of CC-4047 in the treatment of Primary, Post Polycythemia Vera, or Post Essential Thrombocythemia Myelofibrosis (PMF, post-PV MF, or post-ET MF).

Phase II:

Primary

• Best overall response as determined by International Working Group Criteria over the first 6 cycles (168 days) of study treatment.

Secondary

• Safety (type, frequency, severity [National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0] of adverse events (AEs), and relationship of AEs to CC-4047.

• Duration of response.

• Time to response.

• Best overall response as determined by International Working Group Criteria over the first 12 cycles (336 days) of study treatment.

OUTLINE: Patients receive oral CC-4047. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed at 28 days and then every 6 months for up to 3 years.

Study Design

• Study Type: Interventional
• Actual Enrollment: 77 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I/II, Prospective, Open-Label Study to Determine the Safety and Efficacy of CC-4047 in Patients With Primary, Post Polycythemia Vera, or Post Essential Thrombocythemia Myelofibrosis®
• Actual Study Start Date: May 1, 2008
• Actual Primary Completion Date: Jul 7, 2010
• Actual Study Completion Date: Dec 12, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: CC-4047	Drug: CC-4047; CC-4047: taken orally each day in a 28 day cycle.

Outcome Measures

Primary Outcome Measures

1. Determine the Maximum Tolerated Dose of CC-4047 [The first 28-day cycle of treatment.]

   Starting at a dose level of 2.5 mg/d on days 1-21 in every 28 day cycle, participants were accrued in cohorts of three to assess dose limiting toxicities (DLT) and determine the maximum tolerated dose (MTD). Dose escalation at increments of 0.5 mg/d was done if no subject had a DLT (a grade 4 or higher hematologic toxicity or a grade 3 or higher febrile neutropenia or a grade 3 or higher non-hematologic toxicity) in cycle 1. Subsequent cohorts were treated until the maximum tolerated dose (MTD) was reached (dose level before that which results in a DLT in >1 of 6 subjects). Subsequent participants were treated at the MTD, those without response at the MTD after 3 cycles were lowered to the minimal efficacious dose (MED) of 0.5 mg daily. Here, we are reporting the percentage of participants in Phase I with a DLT at each dose level.

2. Best Overall Response Over the First 6 Cycles of Treatment [Every cycle of treatment for 6 cycles. Each cycle is 28 days.]

   Response evaluation: Complete Remission (CR): Neutrophil count between 1 to 10 x 10^9/L without peripheral blasts in blood or bone marrow. Partial Hematologic Response/Partial Remission (PR): Increase in neutrophil by 50% + above 10^9/L for neutropenia) Clinical Improvement (CI): Increase in Neutrophil count, hemoglobin, platelet count or reduction in blood/marrow blasts.

Secondary Outcome Measures

1. Number of Participants With Treatment Related Adverse Events. [During treatment and every 6 months until 3 years from registration or progression.]

   Adverse events (AE) that are classified as either possibly, probably, or definitely related to study treatment according to the National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE version 3.0). The maximum grade for each type of AE will be recorded for each patient. The number of participants with grade 3 or higher adverse events at least possibly related to study treatment are reported here.

2. Duration of Response Time [Time from response to disease progression, intolerance of study drug, or death.]

   Duration of response is defined as the date at which the patient's objective status is first noted to be a CR, PR or CI to the date progression is documented (if one has occurred) or to the date of last follow-up(for those patients who have not progressed).

3. Time to Response [Time from registration to the first date of response within twelve 28-day cycles of treatment.]

   The time to response is defined as the time from study registration to the first date at which the patient's objective status was classified as a response (CR, PR or CI). In patients who do not achieve a response, time to response will be censored at the patient's last evaluation date. The distribution for each of these event-time variables (duration of response and time to response) will be estimated by Kaplan-Meier curves.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 120 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

DISEASE CHARACTERISTICS:

• Diagnosis of primary and post essential thrombocythemia (ET) or post polycythemia vera (PV) myelofibrosis requiring therapy

• De novo presentation (i.e., agnogenic myeloid metaplasia AND post ET or post PV myelofibrosis)

• Developed after an antecedent history of PV (i.e., post polycythemic myeloid metaplasia) or essential polycythemia (i.e., post thrombocythemic myeloid metaplasia)

• Total hemoglobin < 10 g/dL OR transfusion dependent anemia (defined by a history of ≥ 2 units of red blood cell (RBC) transfusions within the past 28 days for hemoglobin < 8.5 g/dL that was not associated with overt bleeding) OR marked splenomegaly (e.g., ≥ 10 cm below costal margin)

PATIENT CHARACTERISTICS:

• Eastern Cooperative Oncology Group (ECOG) performance status 0-2

• Absolute neutrophil count (ANC) ≥ 500/μL

• Platelet count ≥ 20,000/μL

• Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) ≤ 3 times upper limit of normal (ULN) (≤ 5 times ULN if attributed to hepatic extramedullary hematopoiesis)

• Total bilirubin ≤ 3 times ULN OR direct bilirubin ≤ 2 times ULN

• Serum creatinine ≤ 2.0 mg/dL

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective double-method contraception for ≥ 28 days before, during, and for ≥ 28 days after completion of study treatment

• Agrees to abstain from donating blood, semen, or sperm during and for ≥ 28 days after completion of study treatment

• Willing to undergo transfusion of blood products (if applicable)

• Able to complete questionnaire(s) alone or with assistance

• No known HIV positivity, hepatitis B carrier, or active hepatitis C infection

• No serious medical condition, psychiatric illness, or any other condition, including the presence of laboratory abnormalities, that (as judged by the treating physician) would preclude giving informed consent or participating in the study or confound the ability to interpret data from the study

• No other active malignancies, except basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix or breast

• No active deep vein thrombosis or pulmonary embolism that has not been therapeutically anticoagulated

PRIOR CONCURRENT THERAPY:

• Recovered from all prior therapy

• No prior CC-4047

• More than 28 days since prior growth factors, cytotoxic chemotherapeutic agents (e.g., hydroxyurea or anagrelide), corticosteroids, or experimental drugs or therapies

• No other concurrent experimental drugs or therapies or cytotoxic chemotherapeutic agents (e.g., hydroxyurea or anagrelide) for myelofibrosis

• No concurrent growth factors (including erythropoietin) for myelofibrosis, except G-CSF or pegfilgrastim

• No concurrent chronic use (i.e., > 2 weeks) of more than physiologic doses of corticosteroids (dose equivalent to > 10 mg/day of prednisone)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic	Rochester	Minnesota	United States	55905

Sponsors and Collaborators

• Mayo Clinic
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Ruben A. Mesa, MD, Mayo Clinic
• Study Chair: Ayalew Tefferi, MD, Mayo Clinic

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Mayo Clinic
• ClinicalTrials.gov Identifier: NCT00669578
• Other Study ID Numbers: MC078B; P30CA015083; MC078B; NCI-2009-01331; 07-005317; PO-MMM-PI-0007
• First Posted: Apr 30, 2008
• Last Update Posted: Dec 30, 2019
• Last Verified: Dec 1, 2019

• Keywords provided by Mayo Clinic: secondary myelofibrosis; polycythemia vera; essential thrombocythemia; primary myelofibrosis
• Additional relevant MeSH terms: Polycythemia Vera; Primary Myelofibrosis; Myeloproliferative Disorders; Pomalidomide

Study Results

Participant Flow

Recruitment Details	This study opened June 2008 and accrued 12 Phase I participants and 65 Phase II participants before being closed in January 2010.
Pre-assignment Detail	Participants were accrued to the Phase I portion of this study in each of the 2.5, 3.0, and 3.5 mg dose cohorts. Dose Limiting Toxicities (DLT) were observed at the 3.5 mg level, and the 3 mg level was confirmed as the maximum tolerated dose. However, efficacy was not improved at higher doses and the most effective dose level was deemed 0.5 mg/day.

Arm/Group Title	Phase I	Phase II
Arm/Group Description	Participants were accrued to the Phase I portion of this study in each of the 2.5, 3.0, and 3.5 mg dose cohorts to determine the Maximum Tolerated Dose (MTD). Dose limiting Toxicities (DLT) were observed at the 3.5 mg level, and the 3 mg level was confirmed as the maximum tolerated dose. For this study a DLT was defined as a grade 4 hematologic toxicity, a grade 3 or higher febrile neutropenia, or a grade 3 or higher non-hematologic toxicity.	All patients enrolled to this phase II arm started treatment at 0.5mg/day with CC-4047 every day of each 28 day cycle.
Period Title: Overall Study
STARTED	12	65
COMPLETED	12	65
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Phase II	Phase I	Total
Arm/Group Description	All patients enrolled to this Phase II arm started treatment at 0.5mg/day with CC-4047 every day of each 28 day cycle.	Participants were accrued to the Phase I portion of this study in each of the 2.5, 3.0, and 3.5 mg dose cohorts to determine the Maximum Tolerated Dose (MTD). Dose limiting Toxicities (DLT) were observed at the 3.5 mg level, and the 3 mg level was confirmed as the maximum tolerated dose. For this study a DLT was defined as a grade 4 hematologic toxicity, a grade 3 or higher febrile neutropenia, or a grade 3 or higher non-hematologic toxicity.	Total of all reporting groups
Overall Participants	65	12	77
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	68 (9.7)	66	67
Sex: Female, Male (Count of Participants)
Female	18 27.7%	7 58.3%	25 32.5%
Male	47 72.3%	5 41.7%	52 67.5%
Region of Enrollment (participants) [Number]
United States	65 100%	12 100%	77 100%

Outcome Measures

1. Primary Outcome

Title	Determine the Maximum Tolerated Dose of CC-4047
Description	Starting at a dose level of 2.5 mg/d on days 1-21 in every 28 day cycle, participants were accrued in cohorts of three to assess dose limiting toxicities (DLT) and determine the maximum tolerated dose (MTD). Dose escalation at increments of 0.5 mg/d was done if no subject had a DLT (a grade 4 or higher hematologic toxicity or a grade 3 or higher febrile neutropenia or a grade 3 or higher non-hematologic toxicity) in cycle 1. Subsequent cohorts were treated until the maximum tolerated dose (MTD) was reached (dose level before that which results in a DLT in >1 of 6 subjects). Subsequent participants were treated at the MTD, those without response at the MTD after 3 cycles were lowered to the minimal efficacious dose (MED) of 0.5 mg daily. Here, we are reporting the percentage of participants in Phase I with a DLT at each dose level.
Time Frame	The first 28-day cycle of treatment.

Outcome Measure Data

Analysis Population Description

None of the Phase II participants were evaluable for this endpoint. For the Phase I portion of this study, three participants were accrued at a 2.5 mg/day dose level, six at the 3.0 mg/day dose level, and three at the 3.5 mg/day dose level.

Arm/Group Title	Phase I	Phase II
Arm/Group Description	Participants were accrued to the Phase I portion of this study in each of the 2.5, 3.0, and 3.5 mg dose cohorts to determine the Maximum Tolerated Dose (MTD). Dose limiting Toxicities (DLT) were observed at the 3.5 mg level, and the 3 mg level was confirmed as the maximum tolerated dose. For this study a DLT was defined as a grade 4 hematologic toxicity, a grade 3 or higher febrile neutropenia, or a grade 3 or higher non-hematologic toxicity.	All patients enrolled to this phase II arm started treatment at 0.5mg/day with CC-4047 every day of each 28 day cycle.
Measure Participants	12	0
2.5 mg/day	0 0%
3.0 mg/day	0 0%
3.5 mg/day	66 101.5%

2. Secondary Outcome

Title	Number of Participants With Treatment Related Adverse Events.
Description	Adverse events (AE) that are classified as either possibly, probably, or definitely related to study treatment according to the National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE version 3.0). The maximum grade for each type of AE will be recorded for each patient. The number of participants with grade 3 or higher adverse events at least possibly related to study treatment are reported here.
Time Frame	During treatment and every 6 months until 3 years from registration or progression.

Outcome Measure Data

Analysis Population Description

None of the Phase I participants were used for this primary endpoint. All 65 Phase II participants were evaluable for this endpoint.

Arm/Group Title	Phase II	Phase I
Arm/Group Description	All patients enrolled to this Phase II arm started treatment at 0.5mg/day with CC-4047 every day of each 28 day cycle.	Participants were accrued to the Phase I portion of this study in each of the 2.5, 3.0, and 3.5 mg dose cohorts to determine the Maximum Tolerated Dose (MTD). Dose limiting Toxicities (DLT) were observed at the 3.5 mg level, and the 3 mg level was confirmed as the maximum tolerated dose. For this study a DLT was defined as a grade 4 hematologic toxicity, a grade 3 or higher febrile neutropenia, or a grade 3 or higher non-hematologic toxicity.
Measure Participants	65	0
Grade 3 or Higher	6 9.2%
Grade 4 or Higher	3 4.6%
Grade 5	0 0%

3. Secondary Outcome

Title	Duration of Response Time
Description	Duration of response is defined as the date at which the patient's objective status is first noted to be a CR, PR or CI to the date progression is documented (if one has occurred) or to the date of last follow-up(for those patients who have not progressed).
Time Frame	Time from response to disease progression, intolerance of study drug, or death.

Outcome Measure Data

Analysis Population Description

None of the Phase I participants were evaluable for this endpoint. Sixty-five (65) participants were recruited for the Phase II portion. Results presented here are on the 9 Phase II patients who responded to treatment.

Arm/Group Title	Phase II	Phase I
Arm/Group Description	All patients enrolled to this Phase II arm started treatment at 0.5mg/day with CC-4047 every day of each 28 day cycle.	Participants were accrued to the Phase I portion of this study in each of the 2.5, 3.0, and 3.5 mg dose cohorts to determine the Maximum Tolerated Dose (MTD). Dose limiting Toxicities (DLT) were observed at the 3.5 mg level, and the 3 mg level was confirmed as the maximum tolerated dose. For this study a DLT was defined as a grade 4 hematologic toxicity, a grade 3 or higher febrile neutropenia, or a grade 3 or higher non-hematologic toxicity.
Measure Participants	9	0
Median (95% Confidence Interval) [Months]	5.6

4. Secondary Outcome

Title	Time to Response
Description	The time to response is defined as the time from study registration to the first date at which the patient's objective status was classified as a response (CR, PR or CI). In patients who do not achieve a response, time to response will be censored at the patient's last evaluation date. The distribution for each of these event-time variables (duration of response and time to response) will be estimated by Kaplan-Meier curves.
Time Frame	Time from registration to the first date of response within twelve 28-day cycles of treatment.

Outcome Measure Data

Analysis Population Description

None of the Phase I participants were evaluable for this endpoint. Sixty-five (65) patients were recruited for the Phase II portion. Only 9 of the 65 patients achieved a response. Thus, the median of time to response and the upper limit of 95% confidence interval are not attainable.

Arm/Group Title	Phase II	Phase I
Arm/Group Description	All patients enrolled to this Phase II arm started treatment at 0.5mg/day with CC-4047 every day of each 28 day cycle.	Participants were accrued to the Phase I portion of this study in each of the 2.5, 3.0, and 3.5 mg dose cohorts to determine the Maximum Tolerated Dose (MTD). Dose limiting Toxicities (DLT) were observed at the 3.5 mg level, and the 3 mg level was confirmed as the maximum tolerated dose. For this study a DLT was defined as a grade 4 hematologic toxicity, a grade 3 or higher febrile neutropenia, or a grade 3 or higher non-hematologic toxicity.
Measure Participants	0	0

5. Primary Outcome

Title	Best Overall Response Over the First 6 Cycles of Treatment
Description	Response evaluation: Complete Remission (CR): Neutrophil count between 1 to 10 x 10^9/L without peripheral blasts in blood or bone marrow. Partial Hematologic Response/Partial Remission (PR): Increase in neutrophil by 50% + above 10^9/L for neutropenia) Clinical Improvement (CI): Increase in Neutrophil count, hemoglobin, platelet count or reduction in blood/marrow blasts.
Time Frame	Every cycle of treatment for 6 cycles. Each cycle is 28 days.

Outcome Measure Data

Analysis Population Description

None of the participants from the Phase I cohort were analyzed for this endpoint. All 65 Phase II participants were evaluable for this endpoint and included in the analysis.

Arm/Group Title	Phase II	Phase I
Arm/Group Description	All patients enrolled to this Phase II arm started treatment at 0.5mg/day with CC-4047 every day of each 28 day cycle.	Participants were accrued to the Phase I portion of this study in each of the 2.5, 3.0, and 3.5 mg dose cohorts to determine the Maximum Tolerated Dose (MTD). Dose limiting Toxicities (DLT) were observed at the 3.5 mg level, and the 3 mg level was confirmed as the maximum tolerated dose. For this study a DLT was defined as a grade 4 hematologic toxicity, a grade 3 or higher febrile neutropenia, or a grade 3 or higher non-hematologic toxicity.
Measure Participants	65	0
Complete Remission	0 0%
Partial Remission	0 0%
Clinical Improvement	9 13.8%

Adverse Events

Time Frame	Every 28 day cycle while on treatment (up to 12 cycles).
Adverse Event Reporting Description	The primary endpoint for the Phase I cohort of participants was to determine the MTD based on the frequency of DLTs at increasing dose levels. The adverse events in the Phase I cohort were summarized as the Phase I primary endpoint. Here, we report adverse events of all 65 Phase II participants.
Arm/Group Title	Phase II
Arm/Group Description	All patients enrolled to this Phase II arm started treatment at 0.5mg/day with CC-4047 every day of each 28 day cycle.
All Cause Mortality
	Phase II
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Phase II
	Affected / at Risk (%)	# Events
Total	19/65 (29.2%)
Blood and lymphatic system disorders
Hemoglobin decreased	2/65 (3.1%)	2
Cardiac disorders
Myocardial ischemia	1/65 (1.5%)	1
Gastrointestinal disorders
Diarrhea	1/65 (1.5%)	1
Esophageal varices hemorrhage	1/65 (1.5%)	1
Gastrointestinal disorder	1/65 (1.5%)	1
Lower gastrointestinal hemorrhage	1/65 (1.5%)	1
Upper gastrointestinal hemorrhage	1/65 (1.5%)	1
General disorders
Edema limbs	1/65 (1.5%)	1
Fatigue	1/65 (1.5%)	1
Multi-organ failure	1/65 (1.5%)	1
Immune system disorders
Hypersensitivity	1/65 (1.5%)	1
Infections and infestations
Infectious meningitis	1/65 (1.5%)	1
Pneumonia	4/65 (6.2%)	4
Upper respiratory infection	1/65 (1.5%)	1
Investigations
Leukocyte count decreased	2/65 (3.1%)	2
Neutrophil count decreased	1/65 (1.5%)	1
Platelet count decreased	1/65 (1.5%)	1
Metabolism and nutrition disorders
Tumor lysis syndrome	1/65 (1.5%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnea	1/65 (1.5%)	1
Hypoxia	1/65 (1.5%)	1
Laryngeal edema	1/65 (1.5%)	1
Skin and subcutaneous tissue disorders
Skin ulceration	1/65 (1.5%)	1
Vascular disorders
Hematoma	1/65 (1.5%)	1
Other (Not Including Serious) Adverse Events
	Phase II
	Affected / at Risk (%)	# Events
Total	65/65 (100%)
Blood and lymphatic system disorders
Hemoglobin decreased	53/65 (81.5%)	214
Cardiac disorders
Left ventricular dysfunction	1/65 (1.5%)	1
Endocrine disorders
Hypothyroidism	1/65 (1.5%)	1
Gastrointestinal disorders
Constipation	1/65 (1.5%)	1
Diarrhea	10/65 (15.4%)	19
Nausea	9/65 (13.8%)	16
Vomiting	3/65 (4.6%)	4
General disorders
Edema limbs	1/65 (1.5%)	1
Fatigue	65/65 (100%)	477
Localized edema	1/65 (1.5%)	1
Pain	2/65 (3.1%)	2
Immune system disorders
Hypersensitivity	1/65 (1.5%)	1
Infections and infestations
Skin infection	1/65 (1.5%)	1
Investigations
Alkaline phosphatase increased	1/65 (1.5%)	1
Leukocyte count decreased	15/65 (23.1%)	54
Neutrophil count decreased	27/65 (41.5%)	196
Platelet count decreased	43/65 (66.2%)	274
Metabolism and nutrition disorders
Blood uric acid increased	7/65 (10.8%)	11
Serum potassium increased	2/65 (3.1%)	3
Serum sodium decreased	1/65 (1.5%)	1
Musculoskeletal and connective tissue disorders
Joint effusion	1/65 (1.5%)	1
Pain in extremity	1/65 (1.5%)	1
Nervous system disorders
Peripheral sensory neuropathy	18/65 (27.7%)	81
Renal and urinary disorders
Hemorrhage urinary tract	1/65 (1.5%)	1
Protein urine positive	1/65 (1.5%)	1
Renal failure	2/65 (3.1%)	2
Respiratory, thoracic and mediastinal disorders
Dyspnea	1/65 (1.5%)	1
Skin and subcutaneous tissue disorders
Pruritus	20/65 (30.8%)	36
Skin ulceration	1/65 (1.5%)	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.