A Safety Study of Daratumumab, Ixazomib, and Dexamethasone in Previously Treated Amyloid Light Chain (AL) Amyloidosis

Study of Daratumumab, Ixazomib, and Dexamethasone in Previously Treated Amyloid Light Chain (AL) Amyloidosis



Sponsors


Source

M.D. Anderson Cancer Center

Oversight Info

Has Dmc

No

Is Fda Regulated Drug

Yes

Is Fda Regulated Device

No


Brief Summary

The goal of this clinical research study is to learn if the combination of daratumumab,
ixazomib, and dexamethasone at standard doses can be given safely to patients with amyloid
light chain (AL) amyloidosis.

Researchers also want to learn the recommended dose of the study drug combination.

This is an investigational study. Daratumumab and ixazomib are FDA approved and commercially
available for the treatment of another type of blood cancer called multiple myeloma, although
not in combination. Dexamethasone is FDA approved and commercially available to help prevent
or treat certain side effects. The combination of daratumumab and ixazomib with dexamethasone
is not FDA approved for the treatment of AL amyloidosis. It is currently being used for
research purposes only.

The study doctor can explain how the study drugs are designed to work.

Up to 20 participants will be enrolled in this study. All will take part at MD Anderson.

Detailed Description

Study Drug Administration:

If you are found to be eligible to take part in this study, you will receive daratumumab,
ixazomib, and dexamethasone. All participants will receive the study drugs at the same doses.
Dexamethasone will be given at a lower dose during Cycle 1 and then a higher dose during
Cycles 2 and beyond.

Each cycle is 28 days.

You will receive daratumumab by vein on Days 1, 8, 15, and 22 of Cycles 1-2, then on Days 1
and 15 for Cycles 3-6, and on Day 1 of Cycles 7-12. The first 2 doses will be given over 6½
hours. After that, the doses may be given over 3½ hours if you have no bad reactions.

You will take ixazomib by mouth on Days 1, 8, and 15 of Cycles 1-12. You should take each
dose of ixazomib on an empty stomach (no food or drink) at least 1 hour before or at least 2
hours after food, with about 8 ounces (1 cup) of water.

Swallow the ixazomib capsules whole. Do not break, chew, or open capsules. If you miss or
vomit a dose of study drug at home, do not retake the missed or vomited dose. Wait and take
the next scheduled dose.

Dexamethasone is given as a premedication before your dose of daratumumab to lower the risk
of side effects. You will receive dexamethasone by vein over 15 minutes or by mouth on Days
1, 8, 15, and 22 of Cycle 1. Starting with Cycle 2 and beyond, dexamethasone will be given as
a premedication before each dose of daratumumab and then again the next day. During weeks
when you do not have a daratumumab dose scheduled, you will receive dexamethasone as a single
dose 1 time a week.

You should bring any empty bottles and any unused study drug to the clinic at each visit. You
will be given a diary to record when you take your study drug each day.

Study Visits:

On Day 1 of Cycles 1-12:

- You will have a physical exam.

- Blood (about 4 tablespoons) will be drawn and a 24-hour urine sample will be collected
for routine tests.

On Day 8, 15, and 22 of Cycles 1 and 2 and Day 15 of Cycle 3-6, blood (about 1-2 tablespoons)
will be drawn for routine tests.

These tests may be repeated if the doctor thinks it is needed.

Length of Study:

You may continue taking the study drugs for up to 12 cycles, as long as the doctor thinks it
is in your best interest. You will no longer be able to take the study drugs if the disease
gets worse, if intolerable side effects occur, or if you are unable to follow study
directions.

Your participation on the study will be over after your last follow-up visit.

Follow-up Visits:

About 30 days after your last study drug dose:

- You will have a physical exam.

- Blood (about 4 tablespoons) will be drawn and a 24-hour urine sample will be collected
for routine tests.

- You will have an ECHO to check your heart function.

If you stop the study drugs and the disease has not gotten worse, blood (about 4 tablespoons)
will be drawn and a 24-hour urine sample will be collected for routine tests every 90 days
(+/- 30 days). The testing will stop after 24 months or if the disease gets worse, whichever
comes first.

Overall Status

Not yet recruiting

Start Date

2018-02-01

Completion Date

2022-02-01

Primary Completion Date

2021-02-01

Phase

Phase 1

Study Type

Interventional

Primary Outcome

Measure

Time Frame

Dose Limiting Toxicity (DLT) of Daratumumab, Ixazomib, and Dexamethasone in Previously Treated Amyloid Light Chain (AL) Amyloidosis
Start of drug combination up to 30 days after drug combination stopped
Phase 2 Dose (RP2D) of Daratumumab, Ixazomib, and Dexamethasone in Previously Treated Amyloid Light Chain (AL) Amyloidosis
Start of drug combination up to 30 days after drug combination stopped

Secondary Outcome

Measure

Time Frame

Hematologic Response Rate of Daratumumab, Ixazomib, and Dexamethasone in Previously Treated Amyloid Light Chain (AL) Amyloidosis
Start of drug combination up to 30 days after drug combination stopped

Enrollment

20

Conditions


Intervention

Intervention Type

Drug

Intervention Name


Description

Cycles 1-2 (28-day cycle): Daratumumab 16 mg/kg by vein on Days 1, 8, 15, and 22.
Cycles 3-6 (28-day cycle): Daratumumab 16 mg/kg by vein on Days 1 and 15.
Cycles 7-12 (28-day cycle): Daratumumab 16 mg/kg by vein on Days 1.

Arm Group Label

Daratumumab + Ixazomib + Dexamethasone


Intervention Type

Drug

Intervention Name


Description

Cycles 1-2 (28-day cycle): Ixazomib 4 mg by mouth on Days 1, 8, and 15 (3 mg if CrCl < 30 mL/min).
Cycles 3-6 (28-day cycle): Ixazomib 4 mg by mouth on Days 1, 8, and 15 (3 mg if CrCl < 30 mL/min).
Cycles 7-12 (28-day cycle): Ixazomib 4 mg by mouth on Days 1, 8, and 15 (3 mg if CrCl < 30 mL/min).

Arm Group Label

Daratumumab + Ixazomib + Dexamethasone

Other Name

MLN 9708

MLN9708



Intervention Type

Drug

Intervention Name


Description

Dexamethasone 20 mg by vein or by mouth on Days 1, 8, 15, and 22 of Cycle 1. Starting with Cycle 2 and beyond if 20 mg tolerated, dose-escalated to 40 mg.

Arm Group Label

Daratumumab + Ixazomib + Dexamethasone

Other Name

Decadron



Eligibility

Criteria

Inclusion Criteria:

1. Diagnosis of primary systemic AL amyloidosis of tissue as determined by: a. Congo red
staining of tissue showing apple green birefringence AND b. Clonal plasma cell
disorder as determined by: i. Immunohistochemistry, in situ hybridization (ISH) or
flow cytometry demonstrating kappa or lambda light chain restriction on bone marrow
biopsy AND/OR ii. Monoclonal protein on serum or urine electrophoresis/immunofixation
OR abnormal free light chain ratio

2. Relapsed and/or refractory disease as defined by: a. Clonal relapse after at least one
previous line of therapy or high-dose chemotherapy and autologous stem cell
transplantation OR b. Refractory disease to prior therapy defined as less than a
hematologic very good partial response (VGPR). If previous therapy was autologous stem
cell transplant (SCT), must be >/=3 months after SCT.

3. Measurable disease defined by: a. Monoclonal protein in the serum or urine by
immunofixation OR plasmacytosis of bone marrow with monoclonal staining for kappa or
lambda light-chain isotype b. dFLC >/= 50mg/L (dFLC=difference in involved and
uninvolved serum free light-chain levels)

4. Male or female patients 18 years or older

5. Voluntary written consent must be given before performance of any study related
procedure not part of standard medical care, with the understanding that consent may
be withdrawn by the patient at any time without prejudice to future medical care.

6. Female patients who: * Are postmenopausal for at least 1 year before the screening
visit, OR * Are surgically sterile, OR * If they are of childbearing potential, agree
to practice 2 effective methods of contraception, at the same time, from the time of
signing the informed consent form through 90 days after the last dose of study drug,
OR * Agree to practice true abstinence when this is in line with the preferred and
usual lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation,
symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of
contraception.)

7. Male patients, even if surgically sterilized (ie, status post-vasectomy), must agree
to one of the following: * Agree to practice effective barrier contraception during
the entire study treatment period and through 90 days after the last dose of study
drug, OR * Agree to practice true abstinence when this is in line with the preferred
and usual lifestyle of the subject. (Periodic abstinence (eg, calendar, ovulation,
symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of
contraception.)

8. Eastern Cooperative Oncology Group (ECOG) performance status and/or other performance
status 0, 1, or 2.

9. 8. Patients must meet the following clinical laboratory criteria: * Absolute
neutrophil count (ANC) >/= 1,000/mm^3 and platelet count >/= 75,000/mm^3. Platelet
transfusions to help patients meet eligibility criteria are not allowed within 3 days
before study enrollment. * Total bilirubin range (ULN). * Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) 3 x ULN. * Calculated creatinine clearance >/= 10 mL/min

Exclusion Criteria:

1. Non-AL amyloidosis

2. Clinically overt myeloma a.) Lytic bone lesions or biopsy proven plasmacytoma b.)
Hypercalcemia (corrected for albumin) > 11 mg/dL unexplained by other causes

3. Clinically significant cardiac disease defined by any of the following criteria: a.)
New York Heart Association (NYHA) Class IV heart failure b.) N-terminal prohormone of
brain natriuretic peptide (NT-ProBNP) > 8500 ng/L c.) Symptomatic orthostatic
hypotension with supine systolic blood pressure < 90 mm Hg d.) Unstable cardiac
arrhythmia e.) Unstable angina f.) Myocardial infarction within the past 6 months.

4. Severe obstructive airway disease defined by forced expiratory volume at one second
(FEV1) < 50%

5. Female patients who are lactating or have a positive serum pregnancy test during the
screening period.

6. Failure to have fully recovered (ie, of prior chemotherapy.

7. Major surgery within 14 days before enrollment.

8. Radiotherapy within 14 days before enrollment. If the involved field is small, 7 days
will be considered a sufficient interval between treatment and administration of the
ixazomib.

9. Infection requiring systemic intravenous antibiotic therapy or other serious infection
within 14 days before study enrollment.

10. Systemic treatment, within 14 days before the first dose of DId, with strong CYP3A
inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital),
or use of Ginkgo biloba or St. John's wort.

11. Ongoing or active systemic infection, active hepatitis B or C virus infection, or
known human immunodeficiency virus (HIV) positive.

12. Any serious medical or psychiatric illness that could, in the investigator's opinion,
potentially interfere with the completion of treatment according to this protocol.

13. Known allergy to any of the study medications, their analogues, or excipients in the
various formulations of any agent.

14. Known GI disease or GI procedure that could interfere with the oral absorption or
tolerance of ixazomib including difficulty swallowing.

15. Diagnosed or treated for another malignancy within 2 years before study enrollment or
previously diagnosed with another malignancy and have any evidence of residual
disease. Patients with nonmelanoma skin cancer or carcinoma in situ of any type are
not excluded if they have undergone complete resection.

16. Patient has >/= Grade 3 peripheral neuropathy, or Grade 2 with pain on clinical
examination during the screening period.

17. Participation in other clinical trials, including those with other investigational
agents not included in this trial, within 30 days of the start of this trial and
throughout the duration of this trial.

18. Patients that have previously been treated with daratumumab or ixazomib, or
participated in a study with ixazomib whether treated with ixazomib or not.

Gender

All

Minimum Age

18 Years

Maximum Age

N/A

Healthy Volunteers

No


Overall Official

Last Name

Role

Affiliation

Hans C. Lee, MD
Principal Investigator
M.D. Anderson Cancer Center

Overall Contact

Last Name

Hans C. Lee, MD

Phone

713-792-2860

Email



Location

Facility

Status

Contact

University of Texas MD Anderson Cancer Center
Houston Texas 77030 United States
Not yet recruiting
Last Name: Clinical Research Operations
Email: [email protected]

Location Countries

Country

United States


Verification Date

2017-09-01

Lastchanged Date

2017-09-13

Firstreceived Date

2017-09-13

Responsible Party

Responsible Party Type

Sponsor


Keywords


Has Expanded Access

No

Condition Browse


Number Of Arms

1

Intervention Browse

Mesh Term

Dexamethasone acetate

Dexamethasone

Ixazomib

Daratumumab

BB 1101

Glycine

Antibodies, Monoclonal



Arm Group

Arm Group Label

Daratumumab + Ixazomib + Dexamethasone

Arm Group Type

Experimental

Description

Daratumumab by vein on Days 1, 8, 15, and 22 of Cycles 1-2, then on Days 1 and 15 for Cycles 3-6, and on Day 1 of Cycles 7-12.
Ixazomib by mouth on Days 1, 8, and 15 of Cycles 1-12.
Dexamethasone by vein or by mouth on Days 1, 8, 15, and 22 of Cycle 1. Starting with Cycle 2 and beyond, Dexamethasone given as a premedication before each dose of Daratumumab and then again the next day. During weeks when no Daratumumab dose scheduled, Dexamethasone as a single dose 1 time a week.


Firstreceived Results Date

N/A

Firstreceived Results Disposition Date

N/A

Study Design Info

Intervention Model

Single Group Assignment

Primary Purpose

Treatment

Masking

None (Open Label)



ClinicalTrials.gov processed this data on September 14, 2017

Conditions

Conditions usually refer to a disease, disorder, syndrome, illness, or injury. In ClinicalTrials.gov, conditions include any health issue worth studying, such as lifespan, quality of life, health risks, etc.
Interventions

Interventions refer to the drug, vaccine, procedure, device, or other potential treatment being studied. Interventions can also include less intrusive possibilities such as surveys, education, and interviews.
Study Phase

Most clinical trials are designated as phase 1, 2, 3, or 4, based on the type of questions that study is seeking to answer:

In Phase 1 (Phase I) clinical trials, researchers test a new drug or treatment in a small group of people (20-80) for the first time to evaluate its safety, determine a safe dosage range, and identify side effects.

In Phase 2 (Phase II) clinical trials, the study drug or treatment is given to a larger group of people (100-300) to see if it is effective and to further evaluate its safety.

In Phase 3 (Phase III) clinical trials, the study drug or treatment is given to large groups of people (1,000-3,000) to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the drug or treatment to be used safely.

In Phase 4 (Phase IV) clinical trials, post marketing studies delineate additional information including the drug's risks, benefits, and optimal use.

These phases are defined by the Food and Drug Administration in the Code of Federal Regulations.



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