Perifosine in Patients With Relapsed/Refractory Waldenstrom's Macroglobulinemia

• Sponsor: Dana-Farber Cancer Institute (Other)
• Overall Status: Completed
• CT.gov ID: NCT00422656
• Collaborator: (none)
• Enrollment: 37
• Location: 1
• Arm: 1
• Duration (Months): 74
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

Waldenström's Macroglobulinemia (lymphoplasmacytic lymphoma, WM) remains incurable with limited therapeutic options and notably absent FDA approved therapy with any WM indication. Therefore, there is a need to identify new therapeutic agents for WM patients both in the upfront and relapsed/refractory setting. The purpose of this research study is to assess the efficacy of perifosine in patients with relapsed or refractory WM.

Condition or Disease	Intervention/Treatment	Phase
Waldenstrom's Macroglobulinemia	Drug: Perifosine	Phase 2

Detailed Description

Perifosine is a drug that in particular inhibits Akt thought to be important for initiation and progression of malignancies, specifically in lymphomas. In laboratory experiments of WM and lymphoma cell lines, perifosine has shown to have cytotoxic and anti-proliferative activity as a single agent. This drug has been used in clinical research studies of other types of cancers including soft tissue sarcomas, head and neck cancers and prostate cancer. This study uses a two-stage design to evaluate efficacy of perifosine based on overall response (OR). The null and alternative OR rates are 20% and 40%. If 4 or more patients enrolled in the stage one cohort (n=17 patients) achieve OR than accrual will proceed to stage two (n=20 patients). If fewer than 10 ORs are observed then the regimen will be considered ineffective.

Study Design

• Study Type: Interventional
• Actual Enrollment: 37 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Study of Perifosine in Patients With Relapsed/Refractory Waldenstrom's Macroglobulinemia
• Study Start Date: Sep 1, 2006
• Actual Primary Completion Date: Jun 1, 2009
• Actual Study Completion Date: Nov 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Perifosine Patients receive oral perifosine (150 mg) daily each cycle. Cycle duration is 28 days. After cycle 2, response is assessed and patients with stable or responding disease can continue for another 4 cycles or until disease progression (PD). Protocol treatment duration is 6 cycles but patients may receive perifosine maintenance per investigator discretion in absence of PD.	Drug: Perifosine; Other Names: KRX-0401

Outcome Measures

Primary Outcome Measures

1. Overall Response (OR) Rate [Disease was assessed every cycle for the first 12 months and every 3 months thereafter. The median duration of treatment with perifosine was 5.6 months (range, 1.8- 21.5+).]

   OR rate is the percentage of patients achieving Complete Response (CR), Partial Response (PR) or Minimal Response (MR) during treatment based on criteria from the 2nd International Workshop on WM. (Weber D, Treon S, et al. Seminars in Oncology 2003). CR: Disappearance of serum monoclonal IgM protein (IgM M-protein) by immunofixation; no histologic evidence of bone marrow (BM) involvement, resolution of any adenopathy/organomegaly (confirmed by CT scan); PR: At least 50% reduction of IgM M-protein and at least 50% decrease in adenopathy/organomegaly on physical examination or on CT scan; and MR: At least 25% but less than 50% reduction of IgM M-protein by protein electrophoresis. Patients must have no new symptoms or signs of active disease.

Secondary Outcome Measures

1. Time to Progression (TTP) [Disease was assessed every cycle for the first 12 months and every 3 months thereafter. Median follow-up time was 19.5 months and range up to 24 months.]

   TTP estimated using the Kaplan-Meier method is defined as the time from registration to disease progression (PD) based on criteria from the 2nd International Workshop on WM. (Weber D, Treon S, et al. Seminars in Oncology 2003) Patients without PD are censored at time of last disease assessment. PD: At least 25% increase in serum monoclonal IgM protein by electrophoresis confirmed with a second measurement at least 2 weeks apart, or progression of clinically significant findings due to disease (i.e., anemia, thrombocytopenia, leucopenia, bulky adenopathy/organomegaly) or symptoms (unexplained recurrent fever of at least 38.4oC, drenching night sweats, at least 10% body weight less, or hyperviscosity, neuropathy, symptomatic cryoglobulinemia, or amyloidosis) attributable to WM.

2. Progression Free Survival (PFS) [Disease was assessed every cycle for the first 12 months and every 3 months thereafter. Median follow-up time was 19.5 months and range up to 24 months.]

   PFS estimated using the Kaplan-Meier method is defined as the time from registration to death from any cause or disease progression (PD) based on criteria from the 2nd International Workshop on WM. (Weber D, Treon S, et al. Seminars in Oncology 2003) Patients alive without PD are censored at time of last disease assessment. PD: At least 25% increase in serum monoclonal IgM protein by electrophoresis confirmed with a second measurement at least 2 weeks apart, or progression of clinically significant findings due to disease (i.e., anemia, thrombocytopenia, leucopenia, bulky adenopathy/organomegaly) or symptoms (unexplained recurrent fever of at least 38.4oC, drenching night sweats, at least 10% body weight less, or hyperviscosity, neuropathy, symptomatic cryoglobulinemia, or amyloidosis) attributable to WM.

3. Treatment-Related Grade 3-4 Adverse Event Rate [Adverse events were collected every cycle on treatment.The median treatment duration was 5.6 months (range, 1.8-21.5+).]

   The percentage of patients experiencing treatment-related grade 3-4 adverse events based on CTCAEv3 as reported on case report forms.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• 18 years of age or older

• Must have received prior therapy for their WM and have relapsed or refractory WM. Any number of prior therapies is acceptable

• Measurable disease, defined as presence of immunoglobulin M paraprotein with a minimum IgM level of equal to or greater than 2 times the ULN and over 10% of lymphoplasmacytic cells in bone marrow

• ECOG Performance Status 0,1, or 2

• Laboratory values as described in the protocol

• Life expectancy of greater than 12 weeks

Exclusion Criteria:

• Uncontrolled infection

• Other active malignancies

• CNS involvement

• Cytotoxic chemotherapy less than 3 weeks, or biologic therapy less than 2 weeks, or corticosteroids less than 2 weeks prior to registration.

• Other concurrent chemotherapy, immunotherapy, radiotherapy, or any ancillary therapy considered investigational

• Pregnant or nursing women

• Known to be HIV positive

• Radiation therapy less than 2 weeks prior to registration

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02115

Sponsors and Collaborators

• Dana-Farber Cancer Institute

Investigators

• Principal Investigator: Irene Ghobrial, MD, Dana-Farber Cancer Institute

Study Documents (Full-Text)

None provided.

More Information

Publications

• Ghobrial IM, Roccaro A, Hong F, Weller E, Rubin N, Leduc R, Rourke M, Chuma S, Sacco A, Jia X, Azab F, Azab AK, Rodig S, Warren D, Harris B, Varticovski L, Sportelli P, Leleu X, Anderson KC, Richardson PG. Clinical and translational studies of a phase II trial of the novel oral Akt inhibitor perifosine in relapsed or relapsed/refractory Waldenstrom's macroglobulinemia. Clin Cancer Res. 2010 Feb 1;16(3):1033-41. doi: 10.1158/1078-0432.CCR-09-1837. Epub 2010 Jan 26.

• Responsible Party: Irene Ghobrial, MD, Principal Investigator, Dana-Farber Cancer Institute
• ClinicalTrials.gov Identifier: NCT00422656
• Other Study ID Numbers: 06-077
• First Posted: Jan 17, 2007
• Last Update Posted: Dec 26, 2017
• Last Verified: Nov 1, 2017

• Keywords provided by Irene Ghobrial, MD, Principal Investigator, Dana-Farber Cancer Institute: relapsed Waldenstrom's Macroglobulinemia; refractory Waldenstrom's Macroglobulinemia; WM; perifosine
• Additional relevant MeSH terms: Waldenstrom Macroglobulinemia

Study Results

Participant Flow

Recruitment Details	From October 2006 through November 2007, patients enrolled from the Dana-Farber Cancer Institute in Boston, MA as well as at the Community Hospital of Monterey Peninsula in Monterey, CA.

Arm/Group Title	Perifosine
Arm/Group Description	Patients receive oral perifosine (150 mg) daily each cycle. Cycle duration is 28 days. After cycle 2, response is assessed and patients with stable or responding disease can continue for another 4 cycles or until disease progression (PD). Protocol treatment duration is 6 cycles but patients may receive perifosine maintenance per investigator discretion in absence of PD.
Period Title: Overall Study
STARTED	37
COMPLETED	37
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Perifosine
Arm/Group Description	Patients receive oral perifosine (150 mg) daily each cycle. Cycle duration is 28 days. After cycle 2, response is assessed and patients with stable or responding disease can continue for another 4 cycles or until disease progression (PD). Protocol treatment duration is 6 cycles but patients may receive perifosine maintenance per investigator discretion in absence of PD.
Overall Participants	37
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	65
Sex: Female, Male (Count of Participants)
Female	10 27%
Male	27 73%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	36 97.3%
Unknown or Not Reported	1 2.7%
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	1 2.7%
White	36 97.3%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (Count of Participants)
United States	37 100%

Outcome Measures

1. Primary Outcome

Title	Overall Response (OR) Rate
Description	OR rate is the percentage of patients achieving Complete Response (CR), Partial Response (PR) or Minimal Response (MR) during treatment based on criteria from the 2nd International Workshop on WM. (Weber D, Treon S, et al. Seminars in Oncology 2003). CR: Disappearance of serum monoclonal IgM protein (IgM M-protein) by immunofixation; no histologic evidence of bone marrow (BM) involvement, resolution of any adenopathy/organomegaly (confirmed by CT scan); PR: At least 50% reduction of IgM M-protein and at least 50% decrease in adenopathy/organomegaly on physical examination or on CT scan; and MR: At least 25% but less than 50% reduction of IgM M-protein by protein electrophoresis. Patients must have no new symptoms or signs of active disease.
Time Frame	Disease was assessed every cycle for the first 12 months and every 3 months thereafter. The median duration of treatment with perifosine was 5.6 months (range, 1.8- 21.5+).

Outcome Measure Data

Analysis Population Description

The analysis dataset is comprised of all enrolled patients.

Arm/Group Title	Perifosine
Arm/Group Description	Patients receive oral perifosine (150 mg) daily each cycle. Cycle duration is 28 days. After cycle 2, response is assessed and patients with stable or responding disease can continue for another 4 cycles or until disease progression (PD). Protocol treatment duration is 6 cycles but patients may receive perifosine maintenance per investigator discretion in absence of PD.
Measure Participants	37
Number (90% Confidence Interval) [percentage of patients]	38

2. Secondary Outcome

Title	Time to Progression (TTP)
Description	TTP estimated using the Kaplan-Meier method is defined as the time from registration to disease progression (PD) based on criteria from the 2nd International Workshop on WM. (Weber D, Treon S, et al. Seminars in Oncology 2003) Patients without PD are censored at time of last disease assessment. PD: At least 25% increase in serum monoclonal IgM protein by electrophoresis confirmed with a second measurement at least 2 weeks apart, or progression of clinically significant findings due to disease (i.e., anemia, thrombocytopenia, leucopenia, bulky adenopathy/organomegaly) or symptoms (unexplained recurrent fever of at least 38.4oC, drenching night sweats, at least 10% body weight less, or hyperviscosity, neuropathy, symptomatic cryoglobulinemia, or amyloidosis) attributable to WM.
Time Frame	Disease was assessed every cycle for the first 12 months and every 3 months thereafter. Median follow-up time was 19.5 months and range up to 24 months.

Outcome Measure Data

Analysis Population Description

The analysis dataset is comprised of all enrolled patients.

Arm/Group Title	Perifosine
Arm/Group Description	Patients receive oral perifosine (150 mg) daily each cycle. Cycle duration is 28 days. After cycle 2, response is assessed and patients with stable or responding disease can continue for another 4 cycles or until disease progression (PD). Protocol treatment duration is 6 cycles but patients may receive perifosine maintenance per investigator discretion in absence of PD.
Measure Participants	37
Median (90% Confidence Interval) [months]	12.6

3. Secondary Outcome

Title	Progression Free Survival (PFS)
Description	PFS estimated using the Kaplan-Meier method is defined as the time from registration to death from any cause or disease progression (PD) based on criteria from the 2nd International Workshop on WM. (Weber D, Treon S, et al. Seminars in Oncology 2003) Patients alive without PD are censored at time of last disease assessment. PD: At least 25% increase in serum monoclonal IgM protein by electrophoresis confirmed with a second measurement at least 2 weeks apart, or progression of clinically significant findings due to disease (i.e., anemia, thrombocytopenia, leucopenia, bulky adenopathy/organomegaly) or symptoms (unexplained recurrent fever of at least 38.4oC, drenching night sweats, at least 10% body weight less, or hyperviscosity, neuropathy, symptomatic cryoglobulinemia, or amyloidosis) attributable to WM.
Time Frame	Disease was assessed every cycle for the first 12 months and every 3 months thereafter. Median follow-up time was 19.5 months and range up to 24 months.

Outcome Measure Data

Analysis Population Description

The analysis dataset is comprised of all enrolled patients.

Arm/Group Title	Perifosine
Arm/Group Description	Patients receive oral perifosine (150 mg) daily each cycle. Cycle duration is 28 days. After cycle 2, response is assessed and patients with stable or responding disease can continue for another 4 cycles or until disease progression (PD). Protocol treatment duration is 6 cycles but patients may receive perifosine maintenance per investigator discretion in absence of PD.
Measure Participants	37
Median (90% Confidence Interval) [months]	12.6

4. Secondary Outcome

Title	Treatment-Related Grade 3-4 Adverse Event Rate
Description	The percentage of patients experiencing treatment-related grade 3-4 adverse events based on CTCAEv3 as reported on case report forms.
Time Frame	Adverse events were collected every cycle on treatment.The median treatment duration was 5.6 months (range, 1.8-21.5+).

Outcome Measure Data

Analysis Population Description

The analysis dataset is comprised of all enrolled patients.

Arm/Group Title	Perifosine
Arm/Group Description	Patients receive oral perifosine (150 mg) daily each cycle. Cycle duration is 28 days. After cycle 2, response is assessed and patients with stable or responding disease can continue for another 4 cycles or until disease progression (PD). Protocol treatment duration is 6 cycles but patients may receive perifosine maintenance per investigator discretion in absence of PD.
Measure Participants	37
Number (90% Confidence Interval) [percentage of patients]	35

Adverse Events

Time Frame	Adverse events were collected every cycle on treatment.The median treatment duration was 5.6 months (range, 1.8-21.5+).
Adverse Event Reporting Description	Maximum grade toxicity by type was first calculated. Serious AEs were defined as events with treatment attribution of possibly, probably or definitely and grade 3 or higher per CTCAEv3. All remaining events regardless of treatment attribution were classified as Other AEs. No further data is available to specify classification of other beyond the general term.
Arm/Group Title	Perifosine
Arm/Group Description	Patients receive oral perifosine (150 mg) daily each cycle. Cycle duration is 28 days. After cycle 2, response is assessed and patients with stable or responding disease can continue for another 4 cycles or until disease progression (PD). Protocol treatment duration is 6 cycles but patients may receive perifosine maintenance per investigator discretion in absence of PD.
All Cause Mortality
	Perifosine
	Affected / at Risk (%)	# Events
Total	0/37 (0%)
Serious Adverse Events
	Perifosine
	Affected / at Risk (%)	# Events
Total	14/37 (37.8%)
Blood and lymphatic system disorders
Hemoglobin	1/37 (2.7%)
Hypokalemia	1/37 (2.7%)
Lymphopenia	1/37 (2.7%)
Eye disorders
Vision-blurred	1/37 (2.7%)
Eye, pain	1/37 (2.7%)
Gastrointestinal disorders
Diarrhea w/o prior colostomy	1/37 (2.7%)
Gastritis/Dyspepsia	1/37 (2.7%)
General disorders
Fatigue	1/37 (2.7%)
Infections and infestations
Infection Gr0-2 neut, bronchus	1/37 (2.7%)
Investigations
Leukocytes	5/37 (13.5%)
Neutrophils	6/37 (16.2%)
Musculoskeletal and connective tissue disorders
Arthritis	2/37 (5.4%)
Other (Not Including Serious) Adverse Events
	Perifosine
	Affected / at Risk (%)	# Events
Total	37/37 (100%)
Blood and lymphatic system disorders
Hemoglobin	26/37 (70.3%)
Cardiac disorders
Palpitations	2/37 (5.4%)
Ear and labyrinth disorders
Tinnitus	2/37 (5.4%)
Hearing-other	1/37 (2.7%)
Eye disorders
Vision-blurred	8/37 (21.6%)
Ocular-other	2/37 (5.4%)
Eye, pain	4/37 (10.8%)
Gastrointestinal disorders
Constipation	13/37 (35.1%)
Diarrhea w/o prior colostomy	30/37 (81.1%)
Distention/bloating, abdominal	2/37 (5.4%)
Dry mouth	1/37 (2.7%)
Flatulence	1/37 (2.7%)
Gastritis	8/37 (21.6%)
Dyspepsia	10/37 (27%)
Hemorrhoids	1/37 (2.7%)
Muco/stomatitis (symptom) oral cavity	2/37 (5.4%)
Nausea	30/37 (81.1%)
Vomiting	25/37 (67.6%)
Oral cavity, hemorrhage	1/37 (2.7%)
Rectum, hemorrhage	2/37 (5.4%)
Abdomen, pain	3/37 (8.1%)
Stomach, pain	4/37 (10.8%)
General disorders
Fatigue	27/37 (73%)
Fever w/o neutropenia	3/37 (8.1%)
Rigors/chills	1/37 (2.7%)
Edema limb	2/37 (5.4%)
Pain-other	2/37 (5.4%)
Flu-like syndrome	3/37 (8.1%)
Infections and infestations
Infection Gr0-2 neut, eye NOS	1/37 (2.7%)
Infection Gr0-2 neut, lung	1/37 (2.7%)
Infection Gr0-2 neut, skin	1/37 (2.7%)
Infection Gr0-2 neut, upper airway	1/37 (2.7%)
Infection w/ unk ANC oral cavity/gums	1/37 (2.7%)
Infection w/ unk ANC upper airway NOS	1/37 (2.7%)
Infection Gr0-2 neut, middle ear	1/37 (2.7%)
Infection-other	2/37 (5.4%)
Injury, poisoning and procedural complications
Fracture	1/37 (2.7%)
Investigations
Haptoglobin	2/37 (5.4%)
Leukocytes	20/37 (54.1%)
Lymphopenia	4/37 (10.8%)
Neutrophils	19/37 (51.4%)
Platelets	3/37 (8.1%)
Weight gain	2/37 (5.4%)
Weight loss	10/37 (27%)
INR	1/37 (2.7%)
Alkaline phosphatase	5/37 (13.5%)
ALT, SGPT	3/37 (8.1%)
AST, SGOT	4/37 (10.8%)
Bilirubin	7/37 (18.9%)
Creatinine	9/37 (24.3%)
Metabolism and nutrition disorders
Anorexia	2/37 (5.4%)
Dehydration	1/37 (2.7%)
Hypoalbuminemia	24/37 (64.9%)
Alkalosis	1/37 (2.7%)
Bicarbonate	14/37 (37.8%)
Hypercalcemia	3/37 (8.1%)
Hypocalcemia	17/37 (45.9%)
Hyperglycemia	28/37 (75.7%)
Hypoglycemia	6/37 (16.2%)
Hypermagnesemia	1/37 (2.7%)
Hyperkalemia	1/37 (2.7%)
Hypokalemia	4/37 (10.8%)
Hypernatremia	19/37 (51.4%)
Hyponatremia	6/37 (16.2%)
Hyperuricemia	1/37 (2.7%)
Musculoskeletal and connective tissue disorders
Arthritis	3/37 (8.1%)
Joint effusion	1/37 (2.7%)
Musculoskeletal/soft tissue-other	2/37 (5.4%)
Back, pain	6/37 (16.2%)
Bone, pain	3/37 (8.1%)
Extremity-limb, pain	5/37 (13.5%)
Joint, pain	6/37 (16.2%)
Nervous system disorders
Taste disturbance	1/37 (2.7%)
Cognitive disturbance	1/37 (2.7%)
Dizziness	2/37 (5.4%)
Extrapyramidal movement	1/37 (2.7%)
Memory impairment	1/37 (2.7%)
Neuropathy-sensory	9/37 (24.3%)
Seizure	1/37 (2.7%)
Head/headache	9/37 (24.3%)
Sinus, pain	1/37 (2.7%)
Psychiatric disorders
Insomnia	1/37 (2.7%)
Confusion	3/37 (8.1%)
Depression	1/37 (2.7%)
Psychosis	1/37 (2.7%)
Libido	2/37 (5.4%)
Renal and urinary disorders
Hemoglobinuria	2/37 (5.4%)
Urinary frequency/urgency	1/37 (2.7%)
Respiratory, thoracic and mediastinal disorders
Nose, hemorrhage	5/37 (13.5%)
Throat/pharynx/larynx, pain	2/37 (5.4%)
Cough	3/37 (8.1%)
Dyspnea	1/37 (2.7%)
Obstruction, airway-bronchus	1/37 (2.7%)
Voice changes/dysarthria	1/37 (2.7%)
Skin and subcutaneous tissue disorders
Odor (patient odor)	1/37 (2.7%)
Sweating	8/37 (21.6%)
Dry skin	2/37 (5.4%)
Pruritus/itching	2/37 (5.4%)
Rash/desquamation	2/37 (5.4%)
Rash: acne/acneiform	2/37 (5.4%)
Skin-other	2/37 (5.4%)
Vascular disorders
Hypertension	1/37 (2.7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT 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.