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A Phase I/II Clinical Trial of Pomalidomide With Melphalan and Dexamethasone in Patients With Newly Diagnosed Untreated Systemic AL Amyloidosis


Phase 1/Phase 2
18 Years
N/A
Not Enrolling
Both
Myeloma

Thank you

Trial Information

A Phase I/II Clinical Trial of Pomalidomide With Melphalan and Dexamethasone in Patients With Newly Diagnosed Untreated Systemic AL Amyloidosis


Study Groups:

If you are found to be eligible to take part in this study, you will be assigned to a dose
level of pomalidomide, based on when you join this study. Up to 4 dose levels of
pomalidomide will be tested for the Phase I portion of this study. Up to 30 participants
will be enrolled at each dose level in the Phase I portion, and up to 24 participants will
be enrolled in Phase II. The first group of participants will receive the lowest dose
level. Each new group will receive a higher dose than the group before it, if no
intolerable side effects were seen. This will continue until the highest tolerable dose of
pomalidomide is found.

If you are enrolled in the Phase II portion, you will receive pomalidomide at the highest
dose that was tolerated in the Phase I portion.

All participants will receive the same dose level of dexamethasone and melphalan. If
intolerable side effects are seen at the lowest dose level, then the melphalan dose will be
lowered.

Study Drug Administration:

Each cycle is 28 days.

Treatment Phase:

You will take pomalidomide pills by mouth on Days 1-21 of each cycle. You should take each
dose of pomalidomide at about the same time every day. Swallow the pomalidomide capsules
whole with water at the same time each day. Pomalidomide should be taken without food (at
least 2 hours before or 2 hours after a meal). Do not break, chew, or open the capsules. If
you miss a dose of pomalidomide, take it as soon as you remember on the same day. If you
miss taking your dose for the entire day, take your regular dose the next scheduled day (DO
NOT take double your regular dose to make up for the missed dose). You should tell the
study doctor and/or nurse right away about any missed doses of pomalidomide. If you take
more than the prescribed dose of pomalidomide, you should seek emergency medical care, if
needed, and contact the study staff right away. You will need to return any unused
pomalidomide and empty bottles to the clinic at each study visit.

On Days 1-4 of each cycle, you will take melphalan pills by mouth one time each day. You
should take melphalan in the morning at least 2 hours before or after a meal.

You will take dexamethasone pills on Days 1-4 of each cycle.

You will be given standard drugs to help decrease the risk of side effects. You may ask the
study staff for information about how the drugs are given and their risks. You will receive
a blood thinner to prevent blood clots. The study doctor will decide what type of blood
thinner you will receive.

Maintenance Phase:

You will take pomalidomide pills by mouth on Days 1-28 of each cycle during the maintenance
phase. You should take each dose of pomalidomide at about the same time every day. Swallow
the pomalidomide capsules whole with water, at the same time each day. Do not break, chew,
or open the capsules. If you miss a dose of pomalidomide, take it as soon as you remember
on the same day. If you miss taking your dose for the entire day, take your regular dose
the next scheduled day (DO NOT take double your regular dose to make up for the missed
dose). You should tell the study doctor and/or nurse right away about any missed doses of
pomalidomide. If you take more than the prescribed dose of pomalidomide, you should seek
emergency medical care, if needed, and contact the study staff right away. You will need to
return any unused pomalidomide and empty bottles to the clinic at each study visit.

You will also be given a study drug diary. Each time you take pomalidomide at home, you
should write down the date, time, and how many capsules or tablets you took. You should
bring the diary in with you at each study visit for the study doctor to review.

Study Visits:

At every visit you will be asked if you have had any side effects and to list any drugs you
may be taking.

Treatment Phase:

On Day 1 of Cycle 1:

- Your medical history will be reviewed and recorded.

- You will have a physical exam, including measurement of your weight and vital signs.

- Your performance status will be recorded.

- You will be given the study drug diary.

- You will have an EKG and an ECHO.

- You will complete a questionnaire about the feeling in your hands.

- You will be asked about any joint pain you may be experiencing.

- Your lung function will be tested.

- The study doctor will look at your tongue to check the status of the disease.

- You will complete 2 questionnaires about quality-of-life, your general health, your
level of pain, and how the disease affects you. It will take about 15 minutes to
complete the questionnaires.

- Blood (about 1 tablespoon) and urine and/or feces (over 24 hours) will be collected to
check the status of the disease.

- Blood (about 1 tablespoon) will be drawn for genetic testing.

- Blood (about 1 tablespoon) will be drawn for routine tests. If you are able to become
pregnant, a pregnancy test will also be performed.

- If your doctor thinks it is necessary, you will have an ultrasound of the liver and/or
a biopsy of fatty tissue to check the status of the disease.

On Days 8 and 22 of Cycle 1:

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

On Day 15 of Cycle 1:

- Your medical history will be reviewed and recorded.

- You will have a physical exam including measurement of your weight and vital signs.

- Your performance status will be recorded.

- You will have an EKG.

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

- You will complete a questionnaire about your general health, your level of pain, and
how the disease affects you. It will take about 8 minutes to complete the
questionnaire.

On Day 1 of Cycles 2 and beyond:

- Your medical history will be reviewed and recorded.

- You will have a physical exam, including measurement of your weight and vital signs.

- Your performance status will be recorded.

- You will have an EKG and an ECHO.

- You will complete a questionnaire about the feeling in your hands.

- You will be asked about any joint pain you may be experiencing.

- Your lung function will be tested.

- The study doctor will look at your tongue to check the status of the disease.

- You will complete 2 questionnaires about quality-of-life, your general health, your
level of pain, and how the disease affects you. It will take about 15 minutes to
complete the questionnaires.

- Blood (about 1 tablespoon) and urine and/or feces (over 24 hours) will be collected to
check the status of the disease.

- Blood (about 1 tablespoon) will be drawn for genetic testing.

- Blood (about 1 tablespoon) will be drawn for routine tests. If you are able to become
pregnant, a pregnancy test will also be performed.

- If your doctor thinks it is necessary, you will have an ultrasound of the liver, a
biopsy of fatty tissue, and/or a bone marrow aspiration to check the status of the
disease.

On Day 15 of Cycles 2 and beyond:

-You will complete a questionnaire about your general health, your level of pain, and how
the disease affects you. It will take about 8 minutes to complete the questionnaire.

Maintenance Phase:

On Day 1 of Cycle 1:

- Your medical history will be reviewed and recorded.

- You will have a physical exam, including measurement of your weight and vital signs.

- Your performance status will be recorded.

- You will have an ECHO.

- You will complete a questionnaire about the feeling in your hands.

- You will be asked about any joint pain you may be experiencing.

- Your lung function will be tested.

- The study doctor will look at your tongue to check the status of the disease.

- You will complete 2 questionnaires about quality-of-life, your general health, your
level of pain, and how the disease affects you. It will take about 15 minutes to
complete the questionnaires.

- Blood (about 1 tablespoon) and urine and/or feces (over 24 hours) will be collected to
check the status of the disease.

- Blood (about 1 tablespoon) will be drawn for genetic testing.

- Blood (about 1 tablespoon) will be drawn for routine tests. If you are able to become
pregnant, a pregnancy test will also be performed.

- If your doctor thinks it is necessary, you will have an ultrasound of the liver and/or
a biopsy of fatty tissue to check the status of the disease.

On Day 1 of Cycles 2 and beyond:

- Your medical history will be reviewed and recorded.

- You will have a physical exam, including measurement of your weight and vital signs.

- Your performance status will be recorded.

- You will complete 2 questionnaires about quality-of-life, your general health, your
level of pain, and how the disease affects you. It will take about 15 minutes to
complete the questionnaires.

- Blood (about 1 tablespoon) and urine (over 24 hours) will be collected to check the
status of the disease.

- Blood (about 1 tablespoon) will be drawn for routine tests. If you are able to become
pregnant, a pregnancy test will also be performed.

Length of Study:

The Treatment Phase of the study will take about 6 months to complete. If the study doctor
thinks you are benefiting from the study drug combination, you will go into the Maintenance
Phase. You can continue taking the study drug(s) until you experience intolerable side
effects, the disease gets worse, or the study doctor thinks it is in your best interests to
stop.

End-of-Treatment Visit:

If you go off study for any reason, you will have an end-of-treatment visit within 4 weeks
after the last dose of the study drug combination and the following tests and procedures
will be performed:

- Your medical history will be reviewed and recorded.

- You will have a physical exam, including measurement of your weight and vital signs.

- Your performance status will be recorded.

- You will complete a questionnaire about the feeling in your hands.

- You will be asked about any joint pain you may be experiencing.

- Your lung function will be tested.

- The study doctor will look at your tongue to check the status of the disease.

- You will complete 2 questionnaires about quality-of-life, your general health, your
level of pain, and how the disease affects you. It will take about 15 minutes to
complete the questionnaires.

- Blood (about 1 tablespoon) and urine and/or feces (over 24 hours) will be collected to
check the status of the disease.

- Blood (about 1 tablespoon) will be drawn for genetic testing.

- Blood (about 1 tablespoon) will be drawn for routine tests. If you are able to become
pregnant, a pregnancy test will also be performed.

- If your doctor thinks it is necessary, you will have a MRI or a CT scan, a liver
ultrasound, a fatty tissue biopsy, and/or a bone marrow aspiration or biopsy, to check
the status of the disease.

Long Term Follow-Up:

After the end-of-treatment visit, you will be contacted either by telephone or during one of
your standard of care office visits every 3 to 6 months and asked how you are doing. If you
are contacted by phone, the call will take about 5 minutes.

This is an investigational study. Pomalidomide, Melphalan, and Dexamethasone are FDA
approved and commercially available for the treatment of MM. The study drug combination is
not FDA approved or commercially available as a first-line treatment for AL amyloidosis. It
is currently being used for research purposes only.

Up to 54 patients will participate in this multicenter trial. Up to 42 will be enrolled at
MD Anderson.


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 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.
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.

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).

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.

Type of Study:

Interventional

Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Maximum Tolerated Dose (MTD) of Pomalidomide with Melphalan and Dexamethasone (PMD).

Outcome Description:

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.

Outcome Time Frame:

28 days

Safety Issue:

Yes

Principal Investigator

Robert Orlowski, MD, PHD

Investigator Role:

Principal Investigator

Investigator Affiliation:

UT MD Anderson Cancer Center

Authority:

United States: Food and Drug Administration

Study ID:

2012-0215

NCT ID:

NCT01807286

Start Date:

July 2013

Completion Date:

Related Keywords:

  • Myeloma
  • Myeloma
  • Untreated Systemic AL Amyloidosis
  • Amyloid light-chain (AL) amyloidosis
  • Pomalidomide
  • Melphalan
  • Alkeran
  • Dexamethasone
  • Decadron
  • Questionnaires
  • Surveys
  • Amyloidosis
  • Multiple Myeloma
  • Neoplasms, Plasma Cell

Name

Location

UT MD Anderson Cancer CenterHouston, Texas  77030
Tufts Medical CenterBoston, Massachusetts  02111