Pomalidomide With Melphalan and Dexamethasone for Untreated Systemic AL Amyloidosis

Study Description

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Brief Summary:

The goal of this clinical research study is to find the highest tolerable dose of pomalidomide that can be given in combination with melphalan and dexamethasone that can be given to patients with AL amyloidosis. The safety of this drug combination will also be studied.

Pomalidomide is designed to change the body's immune system. It may also interfere with the development of tiny blood vessels that help support tumor growth. This may decrease the growth of cancer cells.

Melphalan is designed to damage the DNA (genetic material) of cells, which may cause cancer cells to die.

Dexamethasone is a corticosteroid that is similar to a natural hormone made by your body. Dexamethasone is often given to Multiple Myeloma (MM) patients in combination with other chemotherapy to treat cancer.

Planned Phase I/II Study terminated early during Phase I portion without continuation to Phase II.

Condition or disease	Intervention/treatment	Phase
Myeloma	Drug: Pomalidomide; Drug: Melphalan; Drug: Dexamethasone; Behavioral: Questionnaires	Phase 1

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Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	3 participants
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	A Phase I/II Clinical Trial of Pomalidomide With Melphalan and Dexamethasone in Patients With Newly Diagnosed Untreated Systemic AL Amyloidosis: Trial Stopped During Phase I
Study Start Date :	January 2014
Actual Primary Completion Date :	February 2016
Actual Study Completion Date :	February 2016

Arms and Interventions

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Arm

Intervention/treatment

Experimental: Pomalidomide + Melphalan + Dexamethasone; Starting dose of Pomalidomide 1 mg/day by mouth on days 1-21. Melphalan 9 mg/m2 by mouth on days 1-4 of every 28-day cycle. Dexamethasone 40 mg/day by mouth on days 1-4. Questionnaires completed at different time points during study.

Drug: Pomalidomide; Phase I: Starting dose of Pomalidomide 1 mg/day by mouth on days 1-21 of a 28 day cycle. Phase II: Starting dose of Pomalidomide maximum tolerated dose from Phase I. Drug: Melphalan; Phase I and II: 9 mg/m2 by mouth on days 1-4 of a 28-day cycle.; Other Name: Alkeran Drug: Dexamethasone; Phase I and II: 40 mg/day by mouth on days 1-4 of a 28 day cycle.; Other Name: Decadron Behavioral: Questionnaires; Questionnaires about the feeling in hands and quality of life completed at different time points during the study.; Other Name: Surveys

Outcome Measures

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Primary Outcome Measures :

1. Maximum Tolerated Dose (MTD) of Pomalidomide with Melphalan and Dexamethasone (PMD). [ Time Frame: 28 days ]
   Maximum tolerated dose defined as highest dose level at which less than 33% of patients experienced dose-limiting toxicities. Dose-limiting toxicities defined as (grade 4 neutropenia lasting more than 7 days despite G-CSF administration, any other grade 4 hematologic toxicity, any grade 3 non-hematologic toxicity, or a new cycle delay beyond a maximum of 4 weeks) in less than 33% of patients during the first cycle of therapy.

Secondary Outcome Measures :

1. Complete Response (CR) Rate [ Time Frame: Response evaluated after a minimum of 2 cycles and a maximum of 6 cycles of 28-day treatment ]
   CR Rate is number of participants with CR out of total study participants. Complete response defined using treatment response in primary systemic amyloidosis from the 10th International Symposium on Amyloid and Amyloidosis where CR: Serum and urine negative for a monoclonal protein by immunofixation; free light chain ratio normal; marrow <5% plasma cells.

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

1. Age >/= 18 years old.
2. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2; Karnofsky >/= 60%
3. Patients must be willing and able to provide voluntary written informed consent, with the understanding that consent may be withdrawn by the subject at any time without prejudice to their future medical care
4. Histologic diagnosis of amyloidosis by Congo red staining of tissue biopsy within 12 months of enrollment.
5. Demonstrable clonal plasma cell disorder based on the presence of an M protein in the serum and/or urine by immunofixation and/or serum free light chain assay, and/or a clonal population of plasma cells in the bone marrow based on kappa/lambda staining of a marrow biopsy.
6. If no demonstrable associated light chain abnormality, then no-light chain amyloidosis should be excluded by checking for transthyretin, fibrinogen A alpha, Amyloid A^3.
7. Patients must have measurable disease, as defined by at least one of the following: Serum or urine immunofixation showing a monoclonal protein and clonal marrow plasmacytosis by marrow biopsy immunohistochemical staining; Free light chains with an abnormal free light chain ratio
8. Symptomatic end organ involvement with amyloidosis as defined previously and to include any one of the following: Renal - albuminuria higher than 0.5 g/day in 24-hour urine analysis; Cardiac - presence of a mean left ventricular wall thickness on echocardiogram more than 11 mm in the absence of a history of hypertension or valvular heart disease, or unexplained low voltage (<0.5 mV) on electrocardiogram; Hepatic - hepatomegaly on physical examination with an alkaline phosphatase level higher than 200 U/L; Gastrointestinal - gastrointestinal amyloid deposits confirmed by tissue biopsy.; Soft-tissue or lymphatic involvement - ascertained based on classic physical exam findings (macroglossia, shoulder pad sign, raccoon eyes, carpal tunnel syndrome, synovial enlargement, firm enlarged lymph nodes) or biopsy.
9. Inclusion Criteria #8 cont... - Nerve - positive history of autonomic or peripheral neuropathy and/or nerve conduction defect documented by electromyogram (EMG)/nerve conduction velocity (NCV) testing.; Skin- measurable skin lesions that are biopsy proven to be amyloidosis
10. No prior therapy for the monoclonal plasma cell disease.
11. Patients must have evidence of adequate bone marrow reserves, as defined by the following pretreatment clinical laboratory values within 14 days of study initiation: Platelet count >/= 100 x 10^9/L without platelet transfusions within 2 weeks of the initiation of treatment; Hemoglobin >/= 8 g/dLwithout red blood cell transfusions within 2 weeks of the initiation of treatment; Absolute neutrophil count (ANC) >/= 1.0x10^9/L without growth factor requirement within 1 week of the initiation of treatment
12. Patients must have evidence of adequate hepatic function, as defined by the following: Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) </= 2.5 times the upper limit of normal; Total bilirubin </= 1.5 times the upper limit of normal
13. Patients must have evidence of adequate renal function, as defined by the following: Serum creatinine within the institutional normal limits, OR, if the creatinine is elevated: Creatinine clearance (CrCl) >/= 30 mL/min., as measured by a 24-hour urine collection, or estimated by the Cockcroft and Gault formula: Female CrCl = (140 - age in years) x weight in kg x 0.85/ 72 x serum creatinine in mg/dL ; Male CrCl = (140 - age in years) x weight in kg x 1.00/72 x serum creatinine in mg/dL
14. Patients must have evidence of adequate cardiac function, as defined by the following: Absence of New York Heart Association (NYHA) class III or IV congestive heart failure; Absence of uncontrolled angina or hypertension; Absence of myocardial infarction in the previous 6 months; Absence of clinically significant bradycardia, or other uncontrolled cardiac arrhythmia defined as grade 3 or 4 according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.0
15. Patients who have undergone any recent major surgery must have done so at least 4 weeks prior to starting therapy with PMD, with the following exceptions:Vertebroplasty and/or kyphoplasty, which must have been performed at least 1 week prior to starting PMD; Planned elective surgery unrelated to the patient's diagnosis of multiple myeloma, such as hernia repair, may be allowed, at the discretion of the principle investigator, as long as it was performed at least 2 weeks prior to starting PMD, and patients have recovered fully from this procedure
16. Male patients must agree to use an adequate method of contraception for the duration of the study since the effects of PMD on the developing human fetus are unknown. If a female partner of a male subject taking Pomalidomide becomes pregnant, the male subject taking Pomalidomide should notify the Investigator immediately. The pregnant female partner should notify their healthcare provider. Female patients must be either post menopausal, free from menses for >/= 2 years, surgically sterilized, or willing to use two adequate barrier methods of contraception to prevent pregnancy, or must agree to abstain from heterosexual activity throughout the study. Female patients of childbearing potential must have a negative serum pregnancy test (Beta-HCG) before receiving the first dose of PMD. The female participant must also follow pregnancy testing requirements as outlined in the POMALYST REMS program.
17. Able to take aspirin (81 or 325 mg) daily as prophylactic anticoagulation (patients intolerant to ASA may use warfarin or low molecular weight heparin).
18. All study participants must be registered into the mandatory POMALYST REMSTM program, and be willing and able to comply with the requirements of the POMALYST REMSTM program.

Exclusion Criteria:

1. Patients who are receiving any concurrent investigational agent with known or suspected activity against amyloidosis
2. Peripheral neuropathy Grade 2 or higher, as defined by National Cancer Institute Common Terminology Criteria (NCI CTC) version 4.
3. Uncontrolled or severe cardiovascular disease including myocardial infarction within 6 months of enrollment, New York Heart Association (NYHA) Class III or IV heart failure uncontrolled angina, or clinically significant pericardial disease.
4. Stage III cardiac amyloidosis with NT-proBNP> 8000 ng/L.
5. Amyloid-specific syndrome, such as carpal tunnel syndrome or skin purpura as the only evidence of disease. The finding of vascular amyloid only in a bone marrow biopsy specimen or in a plasmacytoma is not indicative of systemic amyloidosis.
6. Presence of non-AL amyloidosis
7. Clinically overt multiple myeloma with definite lytic bone lesions.
8. Other malignancy within the past 5 years. Exceptions include basal cell or non-metastatic squamous cell carcinoma of the skin, cervical carcinoma in situ or FIGO Stage 1 carcinoma of the cervix, or breast or prostate cancer that have been stable on hormonal therapy for at least three years.
9. Concurrent medical condition or disease, such as active systemic infection, uncontrolled diabetes, or pulmonary disease, that is likely to interfere with study procedures or results, or that in the opinion of the investigator would constitute a hazard for participating in this study.
10. Use of any investigational drugs within 30 days before initiation of study treatment
11. Human immunodeficiency virus (HIV) positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with pomalidomide. In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated.
12. Patients with active hepatitis B and/or hepatitis C infection
13. Known hypersensitivity to thalidomide or lenalidomide.
14. The development of erythema nodosum if characterized by a desquamating rash while taking thalidomide, pomalidomide or similar drugs.
15. Any prior use of thalidomide, lenalidomide or pomalidomide.
16. Known positive for HIV.

Contacts and Locations

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Locations

United States, Texas
University of Texas MD Anderson Cancer Center
Houston, Texas, United States, 77030

Sponsors and Collaborators

M.D. Anderson Cancer Center

Celgene

Investigators

Principal Investigator:	Robert Orlowski, MD, PHD	M.D. Anderson Cancer Center

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Additional Information:

University of Texas MD Anderson Cancer Center Website 

Responsible Party:	M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier:	NCT01807286 History of Changes
Other Study ID Numbers:	2012-0215; NCI-2013-02276 ( Registry Identifier: NCI CTRP )
First Posted:	March 8, 2013
Last Update Posted:	May 13, 2016
Last Verified:	May 2016

Keywords provided by M.D. Anderson Cancer Center:

Myeloma; Untreated Systemic AL Amyloidosis; Amyloid light-chain (AL) amyloidosis; Pomalidomide; Melphalan	Alkeran; Dexamethasone; Decadron; Questionnaires; Surveys

Additional relevant MeSH terms:

Amyloidosis; Proteostasis Deficiencies; Metabolic Diseases; Dexamethasone acetate; Dexamethasone; Pomalidomide; Melphalan; Thalidomide; BB 1101; Anti-Inflammatory Agents; Antiemetics; Autonomic Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Gastrointestinal Agents

Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Agents; Protease Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Immunosuppressive Agents; Immunologic Factors; Angiogenesis Inhibitors; Angiogenesis Modulating Agents