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A Phase I/II Trial of Carfilzomib, Pegylated Liposomal Doxorubicin, and Dexamethasone for the Treatment of Relapsed/Refractory Multiple Myeloma


Phase 1/Phase 2
18 Years
N/A
Open (Enrolling)
Both
Multiple Myeloma

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Trial Information

A Phase I/II Trial of Carfilzomib, Pegylated Liposomal Doxorubicin, and Dexamethasone for the Treatment of Relapsed/Refractory Multiple Myeloma


Phase I dose-escalation study. Patients receive carfilzomib intravenously (IV) on Days 1,
2, 8, 9, 15, and 16 of Cycles 1-6, and on Days 1, 8, 15, and 22 beginning on Cycle 7 until
disease progression or relapse. Participants treated prior to approval of Amendment 1 will
have carfilzomib administered on Days 1, 2, 8, 9, 15, and 16 during Cycles 1 and 2 and on
Days 1, 8, 15, and 22 beginning on Cycle 3. PLD will be administered on Day 8 during Cycles
1-6. Dexamethasone will be administered on the same schedule as carfilzomib (for patients
treated in part 2 of phase 1 or phase 2). Cycles repeat every 28 days in the absence of
disease progression or unacceptable toxicity.

Phase II will use the MTD from Phase I.


Inclusion Criteria:



- Histologically confirmed diagnosis of multiple myeloma with a measurable disease
parameter at time of screening; a measurable disease parameter is defined as one or
more of the following:

- Serum monoclonal protein >= 0.5 g/dl

- 24 hour urine monoclonal protein >= 0.2 g/24 hour

- Serum free light chain ratio > 5 x normal ratio with an absolute difference of
10mg/dl between the involved and uninvolved free light chain

- Soft tissue plasmacytoma >= 2 cm measurable by either physical examination
and/or applicable radiographs (e.g. magnetic resonance imaging [MRI], computed
tomography [CT], etc)

- Bone Marrow Plasma Cells >= 30%

- Documentation of at least one line of prior myeloma therapy now with relapsed or
refractory disease requiring re-treatment

- At least 18 years of age at the time of signing the informed consent.

- Performance status of Eastern Cooperative Oncology Group (ECOG) =< 2 or Karnofsky >=
60%; participants with lower performance status based solely on bone pain secondary
to multiple myeloma will be eligible

- Required laboratory values

- Alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) and
aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT]) < 2.5 x the upper limit of the institutional normal value (ULN)

- Total bilirubin =< 1.5 x upper limit of normal (ULN)

- Absolute neutrophil count (ANC) >= 1,000

- Hemoglobin >= 8 g/dl

- Platelets >= 50,000

- Creatinine clearance > 15 ml/minute using Cockcroft-Gault formula

- For those participants receiving warfarin (Coumadin), unfractionated heparin, or
low-molecular weight heparin therapy, the applicable coagulation parameter that
is being monitored must be within the accepted therapeutic ranges for those
indications

- Transfusions and/or growth factor dependent participants are not excluded if the
above parameters can be achieved with such support

- Females of childbearing potential (FCBP) must agree to refrain from becoming pregnant
while on study drug and for 3 months after discontinuation from study drug, and must
agree to use adequate contraception including hormonal contraception, (i.e. birth
control pills, etc), barrier method contraception (i.e. condoms), or abstinence
during that time frame; FCBP must agree to regular pregnancy testing during this
timeframe; inclusion of FCBP requires two negative pregnancy tests prior to
enrollment. All women, regardless of age, should be considered FCBP unless they are
surgically sterile (post hysterectomy, post bilateral oophorectomy, etc) or have been
naturally post menopausal for >= 24 consecutive months

- Men engaging in sexual intercourse with a FCBP must agree to use adequate
contraception including hormonal contraception, (i.e. birth control pills, etc),
barrier method contraception (i.e. condoms), or abstinence while on study drug and
for 3 months after discontinuation from study drug

- Ability to understand and willing to sign a written informed consent document

Exclusion Criteria:

- POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and
skin changes)

- Plasma Cell Leukemia

- Waldenstrom's macroglobulinemia

- Pregnant or lactating females

- Use of any anti-myeloma drug therapy within 14 days of initiation of study drug
treatment excluding corticosteroids if given for an indication other than myeloma;
bisphosphonates are not considered anti-myeloma drugs

- Participation in an investigational therapeutic study within 14 days or within 5 drug
half-lives (t1/2) prior to first dose, whichever time is greater

- Radiotherapy to multiple sites or immunotherapy within 14 days before start of
protocol treatment (localized radiotherapy to a single site at least 7 days before
start is permissible)

- Major surgery within 14 days prior to first dose

- Participants in whom the required program of oral (PO) and IV fluid hydration is
contraindicated

- Prior history of a hypersensitivity reaction to PLD, doxorubicin, bortezomib,
carfilzomib, or liposomal drug formulations other than PLD; history of reactions to
liposomal drug formulations other than PLD should be evaluated individually and if
their reactions were felt to have been due to the encapsulated agent, rather than the
liposomal component itself they should be excluded at the discretion of the
investigators

- Participants who are known to have active hepatitis A, B, or C viral infection may
not participate in this study; active disease is defined as participants with a known
viral hepatitis whose liver function tests are elevated

- Known human immunodeficiency virus (HIV)-seropositive and are taking anti-retrovirals
may not participate in this study; participants who are HIV-seropositive and not on
anti-retroviral therapy and who otherwise meet the inclusion/exclusion criteria will
be eligible for the study

- Compromised cardiovascular function defined as any of the following:

- Electrocardiogram (EKG) evidence of acute ischemia

- EKG evidence of medically significant conduction system abnormalities

- History of myocardial infarction within the last 6 months

- Unstable angina pectoris or cardiac arrhythmia

- History of Class 3 or Class 4 New York Heart Association Congestive Heart
Failure within 6 months of enrollment on study

- Left ventricular ejection fraction (LVEF) < 45% by either echocardiography or
radionuclide-based multiple gated acquisition (Echo or MUGA)

- Uncontrolled concurrent illness including: other hematologic or non-hematologic
malignancy, active infection, or uncontrolled diabetes

- Any significant psychological, medical, or surgical condition thought to compromise
the participant, the study, or prevent informed consent

Type of Study:

Interventional

Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

To determine the MTD of carfilzomib and PLD with and without dexamethasone (Phase I - Part 1 & Part 2).

Outcome Description:

MTD is the maximum dose level tested unless dose limiting toxicity (DLT) are observed during Cycle 1. If DLT is observed, MTD will be the next lower dose level.

Outcome Time Frame:

28 days (completion of first cycle)

Safety Issue:

Yes

Principal Investigator

Ravi Vij, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

Washington University School of Medicine

Authority:

United States: Institutional Review Board

Study ID:

201102043

NCT ID:

NCT01246063

Start Date:

May 2012

Completion Date:

November 2015

Related Keywords:

  • Multiple Myeloma
  • Multiple Myeloma
  • Neoplasms, Plasma Cell

Name

Location

Washington University School of MedicineSaint Louis, Missouri  63110