Study of High Dose Carfilzomib in Multiple Myeloma Patients Who Have Progressed On Standard Dose Carfilzomib

• Sponsor: Ajai Chari (Other)
• Overall Status: Completed
• CT.gov ID: NCT01775553
• Collaborator: Amgen (Industry)
• Enrollment: 13
• Location: 1
• Arm: 1
• Duration (Months): 32
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

The purpose of this study is to determine the safety and activity of the investigational drug known as carfilzomib in the treatment of multiple myeloma (MM) when it is given at doses above the usual dose after the standard dosing has become ineffective. The other purpose of this study is to understand what causes the multiple myeloma to become resistant to carfilzomib and whether this can be overcome in the laboratory.

Condition or Disease	Intervention/Treatment	Phase
Relapse Multiple Myeloma; Refractory Multiple Myeloma	Drug: Carfilzomib	Phase 2

Detailed Description

This is an open label, single center, phase II study of high dose carfilzomib. Patients with relapsed or relapsed/refractory myeloma and with progression of disease on standard dosing (20/27 mg/m2) and schedule of carfilzomib will be initially treated at dose level 1, carfilzomib 20/56 mg/m2. During Cycle 1, patients will receive either 20 mg/m2 on days 1,2 (if the subject has not received carfilzomib as part another clinical trial within the last 4 weeks) or 56 mg/m2 (if the subject is enrolling in the present study after progression of disease on carfilzomib within the last month - for example subjects enrolled in CMAP compassionate use carfilzomib). Thereafter, all subjects will receive 56 mg/m2 for the remaining doses given Cycle 1 Day 8 onwards. If a minimal response or better is achieved (and therefore disease response is recaptured) a bone marrow biopsy will be repeated.

If 56 mg/m2 is not tolerated, the dose of carfilzomib will be reduced to dose level -1 i.e. 45 mg/m2. If a subject does not tolerate 45 mg/m2 then the dose would be further reduced to dose level -2 i.e. 36 mg/m2. If the subject does not tolerate 36 mg/m2, then this subject would have to come off study.

Dexamethasone 8 mg po/IV will be administered prior to all carfilzomib doses.

Once a patient develops disease progression on this study, the patient may return to receiving the maximum tolerated dose of carfilzomib by that patient with the addition of a therapeutic dosing of dexamethasone (a total of 20-40 mg weekly). An IMId (e.g. thalidomide or lenalidomide) and/or an alkylator can also be added to carfilzomib 27 or 36 mg/m2 per investigator discretion either concurrent with the addition of dexamethasone or subsequent to disease progression on carfilzomib with concurrent therapeutic dexamethasone.

Study Design

• Study Type: Interventional
• Actual Enrollment: 13 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Recapturing Disease Response: A Phase II Study of High Dose Carfilzomib in Patients With Relapsed or Refractory Multiple Myeloma Who Have Progressed on Standard Dose Carfilzomib
• Study Start Date: Sep 1, 2013
• Actual Primary Completion Date: May 1, 2016
• Actual Study Completion Date: May 1, 2016

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Carfilzomib All patients will receive Carfilzomib

Drug: Carfilzomib; During Cycle 1, patients will receive either 20 mg/m2 on days 1,2 (if the subject has not received carfilzomib as part another clinical trial within the last 4 weeks) or 56 mg/m2 (if the subject is enrolling in the present study after progression of disease on carfilzomib within the last month - for example subjects enrolled in CMAP compassionate use carfilzomib). Thereafter, all subjects will receive 56 mg/m2 for the remaining doses given Cycle 1 Day 8 onwards. Each cycle is 28 days.; Other Names: High Dose Carfilzomib

Outcome Measures

Primary Outcome Measures

1. Safety and Efficacy of High Dose Carfilzomib [up to 4 years]

   The safety and efficacy of high dose carfilzomib who developed disease progression on the standard dosing and schedule of carfilzomib as measured by number of participants with adverse events

Secondary Outcome Measures

1. Progression Free Survival (PFS) [up to 4 years]

2. Overall Response Rate (ORR) [up to 4 years]

   Overall Response Rate defined in categories

3. Duration of Response to High Dose Carfilzomib [up to 4 years]

4. Markers of ER Stress [up to 4 years]

   The markers of ER stress signaling (both apoptotic and prosurvival) in MM cells from patients in this study and to determine if the balance of apoptotic versus prosurvival signaling changes upon recapture of response with carfilzomib dose escalation relative to the time of study entry.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

Disease-related:

1. Multiple myeloma

2. Subjects must have measurable disease, defined as one or both of the following:

3. Serum M-protein ≥ 1.0 g/dL

4. Urine M-protein ≥ 200 mg/24 hours

5. Free light chains: Only in patients without measureable serum and urine M-protein levels: the difference between involved and uninvolved FLC levels must be at least 10 mg/dl.

6. Refractory to the most recently received therapy. Refractory disease is defined as ≤ 25% response or progression during therapy or within 60 days after completion of therapy.

7. Subjects must have progressed on standard dose 20/27 mg/m2 and schedule of carfilzomib without having had any carfilzomib related grade 3 or 4 toxicities.

8. Subjects must have received ≥ 2 prior regimens for relapsed disease. Induction therapy and stem cell transplant will be considered as one regimen

9. Subjects must have received prior treatment with bortezomib, and either thalidomide or lenalidomide

10. Subjects must have received an alkylating agent unless contraindicated. Subjects may have received these agents alone or in combination with other myeloma treatments.

Demographic:

1. Age ≥ 18 years

2. Life expectancy ≥ 3 months

3. Eastern Cooperative Oncology Group (ECOG) performance status 0-2

Laboratory/Radiology

1. Adequate hepatic function, with serum ALT ≤ 3.5 times the upper limit of normal and serum direct bilirubin ≤ 2 mg/dL (34 µmol/L) within 14 days prior to randomization

2. Uric acid, if elevated, must be corrected to within laboratory normal range prior to dosing

3. Absolute neutrophil count (ANC) ≥ 1.0 × 109/L within 14 days prior to randomization independent of G-CSF for ≥ 1 week and pegylated G-CSF for ≥ 2 weeks

4. Hemoglobin ≥ 8 g/dL (80 g/L) within 14 days prior to randomization (subjects may be receiving red blood cell [RBC] transfusions in accordance with institutional guidelines)

5. Screening platelet count ≥ 50 × 109/L independent of platelet transfusions for at least 2 weeks

6. Creatinine clearance (CrCl) ≥ 15 mL/minute within 7 days prior to randomization, either measured or calculated using a standard formula (eg, Cockcroft and Gault)

7. LVEF ≥ 40% within 30 days before Cycle 1 Day 1. 2-D Transthoracic Echocardiogram (ECHO) is the preferred method of evaluation; MUGA is acceptable if ECHO is not available.

Exclusion Criteria:

Disease-related

1. Glucocorticoid therapy (prednisone > 10 mg/day or equivalent) within the last three weeks

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

3. Chemotherapy with approved or investigative anticancer therapeutics including steroid therapy within the three weeks prior to first dose (unless enrolling on this study after progression CMAP compassionate use carfilzomib protocol, in which case subject may proceed with current study treatment on next expected date of treatment)

4. Radiation therapy or immunotherapy in the previous four weeks; localized radiation therapy within 1 week prior to first dose

5. Participation in an investigational therapeutic study within three weeks or within five drug half-lives (t1/2) prior to first dose, whichever time is greater (unless enrolling after progression on CMAP compassionate use carfilzomib protocol)

Concurrent Conditions

1. Pregnant or lactating females

2. Major surgery within 21 days prior to randomization

3. Acute active infection requiring treatment (systemic antibiotics, antivirals, or antifungals) within 14 days prior to randomization

4. Known human immunodeficiency virus infection

5. Known active hepatitis B or C infection

6. Unstable angina or myocardial infarction within 4 months prior to randomization, NYHA Class III or IV heart failure, uncontrolled angina, history of severe coronary artery disease, severe uncontrolled ventricular arrhythmias, sick sinus syndrome, or electrocardiographic evidence of acute ischemia or Grade 3 conduction system abnormalities unless subject has a pacemaker

7. Uncontrolled hypertension or uncontrolled diabetes within 14 days prior to randomization

8. Nonhematologic malignancy within the past 3 years with the exception of a) adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b) carcinoma in situ of the cervix or breast; c) prostate cancer of Gleason Grade 6 or less with stable prostate-specific antigen levels; or d) cancer considered cured by surgical resection or unlikely to impact survival during the duration of the study, such as localized transitional cell carcinoma of the bladder or benign tumors of the adrenal or pancreas

9. Significant neuropathy (Grades 3-4, or Grade 2 with pain) within 14 days prior to randomization

10. Known history of allergy to Captisol® (a cyclodextrin derivative used to solubilize carfilzomib)

11. Contraindication to any of the required concomitant drugs or supportive treatments, including antiviral drugs, or intolerance to hydration due to preexisting pulmonary or cardiac impairment

12. Subjects with pleural effusions requiring thoracentesis or ascites requiring paracentesis within 14 days prior to randomization

13. Any other clinically significant medical disease or condition that, in the Investigator's opinion, may interfere with protocol adherence or a subject's ability to give informed consent

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Icahn School of Medicine at Mount Sinai	New York	New York	United States	10029

Sponsors and Collaborators

• Ajai Chari
• Amgen

Investigators

• Principal Investigator: Ajai Chari, MD, Icahn School of Medicine at Mount Sinai

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Ajai Chari, Associate Professor, Icahn School of Medicine at Mount Sinai
• ClinicalTrials.gov Identifier: NCT01775553
• Other Study ID Numbers: GCO 12-1506; CAR IST 534
• First Posted: Jan 25, 2013
• Last Update Posted: Jun 21, 2017
• Last Verified: May 1, 2017

• Keywords provided by Ajai Chari, Associate Professor, Icahn School of Medicine at Mount Sinai: Relapsed Multiple Myeloma; Refractory Multiple Myeloma; High-Dose Carfilzomib; Standard Dose Carfilzomib; Carfilzomib
• Additional relevant MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell

Study Results

Participant Flow

Arm/Group Title	Carfilzomib
Arm/Group Description	All patients will receive Carfilzomib Carfilzomib: During Cycle 1, patients will receive either 20 mg/m2 on days 1,2 (if the subject has not received carfilzomib as part another clinical trial within the last 4 weeks) or 56 mg/m2 (if the subject is enrolling in the present study after progression of disease on carfilzomib within the last month - for example subjects enrolled in CMAP compassionate use carfilzomib). Thereafter, all subjects will receive 56 mg/m2 for the remaining doses given Cycle 1 Day 8 onwards. Each cycle is 28 days.
Period Title: Overall Study
STARTED	13
COMPLETED	0
NOT COMPLETED	13

Baseline Characteristics

Arm/Group Title	Carfilzomib
Arm/Group Description	All patients will receive Carfilzomib Carfilzomib: During Cycle 1, patients will receive either 20 mg/m2 on days 1,2 (if the subject has not received carfilzomib as part another clinical trial within the last 4 weeks) or 56 mg/m2 (if the subject is enrolling in the present study after progression of disease on carfilzomib within the last month - for example subjects enrolled in CMAP compassionate use carfilzomib). Thereafter, all subjects will receive 56 mg/m2 for the remaining doses given Cycle 1 Day 8 onwards. Each cycle is 28 days.
Overall Participants	13
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	62.9
Sex: Female, Male (Count of Participants)
Female	6 46.2%
Male	7 53.8%
Age >65 years (Count of Participants)
Count of Participants [Participants]	6 46.2%
ECOG Performance Status (Count of Participants)
0	5 38.5%
1	5 38.5%
2	3 23.1%
ISS Staging (Count of Participants)
Stage 1	5 38.5%
Stage 2	5 38.5%
Stage 3	3 23.1%
Immunoglobulin subtype (Count of Participants)
IgG	10 76.9%
IgA	3 23.1%
IgM	0 0%
none	0 0%
Light-chain subtype (Count of Participants)
K	7 53.8%
L	6 46.2%
FISH (Count of Participants)
Normal	7 53.8%
Any abnormality	6 46.2%
Prior therapies since diagnosis (years) [Median (Full Range) ]
Median (Full Range) [years]	7
Number of prior regimens (prior regimens) [Median (Full Range) ]
Median (Full Range) [prior regimens]	5
Prior therapy (participants) [Number]
Dexamethasone : Exposed	13 100%
Dexamethasone : Refractory	13 100%
Thalidomide : Exposed	7 53.8%
Thalidomide : Refractory	1 7.7%
Lenalidomide : Exposed	13 100%
Lenalidomide : Refractory	9 69.2%
Pomalidomide : Exposed	8 61.5%
Pomalidomide : Refractory	8 61.5%
Bortezomib : Exposed	13 100%
Bortezomib : Refractory	9 69.2%
Prior Autologous Stem Cell Transplant (Count of Participants)
Count of Participants [Participants]	7 53.8%
Carfilzomib Regimen Combination (Count of Participants)
Carfilzomib Regimen Combination	13 100%
Weekly 40 mg DEX	11 84.6%
Pomalidomide, DEX	2 15.4%
Cyclophosphamide, DEX	2 15.4%
Ibrutinib, DEX	1 7.7%
Bendamustine	1 7.7%

Outcome Measures

1. Primary Outcome

Title	Safety and Efficacy of High Dose Carfilzomib
Description	The safety and efficacy of high dose carfilzomib who developed disease progression on the standard dosing and schedule of carfilzomib as measured by number of participants with adverse events
Time Frame	up to 4 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Carfilzomib
Arm/Group Description	All patients will receive Carfilzomib Carfilzomib: During Cycle 1, patients will receive either 20 mg/m2 on days 1,2 (if the subject has not received carfilzomib as part another clinical trial within the last 4 weeks) or 56 mg/m2 (if the subject is enrolling in the present study after progression of disease on carfilzomib within the last month - for example subjects enrolled in CMAP compassionate use carfilzomib). Thereafter, all subjects will receive 56 mg/m2 for the remaining doses given Cycle 1 Day 8 onwards. Each cycle is 28 days.
Measure Participants	13
Serious Adverse Events	3 23.1%
Other than Serious Adverse Events	13 100%

2. Secondary Outcome

Title	Progression Free Survival (PFS)
Time Frame	up to 4 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Carfilzomib
Arm/Group Description	All patients will receive Carfilzomib Carfilzomib: During Cycle 1, patients will receive either 20 mg/m2 on days 1,2 (if the subject has not received carfilzomib as part another clinical trial within the last 4 weeks) or 56 mg/m2 (if the subject is enrolling in the present study after progression of disease on carfilzomib within the last month - for example subjects enrolled in CMAP compassionate use carfilzomib). Thereafter, all subjects will receive 56 mg/m2 for the remaining doses given Cycle 1 Day 8 onwards. Each cycle is 28 days.
Measure Participants	12
Median (Full Range) [months]	3.8

3. Secondary Outcome

Title	Overall Response Rate (ORR)
Description	Overall Response Rate defined in categories
Time Frame	up to 4 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Carfilzomib
Arm/Group Description	All patients will receive Carfilzomib Carfilzomib: During Cycle 1, patients will receive either 20 mg/m2 on days 1,2 (if the subject has not received carfilzomib as part another clinical trial within the last 4 weeks) or 56 mg/m2 (if the subject is enrolling in the present study after progression of disease on carfilzomib within the last month - for example subjects enrolled in CMAP compassionate use carfilzomib). Thereafter, all subjects will receive 56 mg/m2 for the remaining doses given Cycle 1 Day 8 onwards. Each cycle is 28 days.
Measure Participants	12
Complete Response	0 0%
Very Good Partial Response	1 7.7%
Partial Response	4 30.8%
Minor Response	2 15.4%
Stable Disease	4 30.8%

4. Secondary Outcome

Title	Duration of Response to High Dose Carfilzomib
Time Frame	up to 4 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Carfilzomib
Arm/Group Description	All patients will receive Carfilzomib Carfilzomib: During Cycle 1, patients will receive either 20 mg/m2 on days 1,2 (if the subject has not received carfilzomib as part another clinical trial within the last 4 weeks) or 56 mg/m2 (if the subject is enrolling in the present study after progression of disease on carfilzomib within the last month - for example subjects enrolled in CMAP compassionate use carfilzomib). Thereafter, all subjects will receive 56 mg/m2 for the remaining doses given Cycle 1 Day 8 onwards. Each cycle is 28 days.
Measure Participants	12
Median (Full Range) [months]	9

5. Secondary Outcome

Title	Markers of ER Stress
Description	The markers of ER stress signaling (both apoptotic and prosurvival) in MM cells from patients in this study and to determine if the balance of apoptotic versus prosurvival signaling changes upon recapture of response with carfilzomib dose escalation relative to the time of study entry.
Time Frame	up to 4 years

Outcome Measure Data

Analysis Population Description

data not collected

Arm/Group Title	Carfilzomib
Arm/Group Description	All patients will receive Carfilzomib Carfilzomib: During Cycle 1, patients will receive either 20 mg/m2 on days 1,2 (if the subject has not received carfilzomib as part another clinical trial within the last 4 weeks) or 56 mg/m2 (if the subject is enrolling in the present study after progression of disease on carfilzomib within the last month - for example subjects enrolled in CMAP compassionate use carfilzomib). Thereafter, all subjects will receive 56 mg/m2 for the remaining doses given Cycle 1 Day 8 onwards. Each cycle is 28 days.
Measure Participants	0

Adverse Events

Arm/Group Title	Carfilzomib
Arm/Group Description	All patients will receive Carfilzomib Carfilzomib: During Cycle 1, patients will receive either 20 mg/m2 on days 1,2 (if the subject has not received carfilzomib as part another clinical trial within the last 4 weeks) or 56 mg/m2 (if the subject is enrolling in the present study after progression of disease on carfilzomib within the last month - for example subjects enrolled in CMAP compassionate use carfilzomib). Thereafter, all subjects will receive 56 mg/m2 for the remaining doses given Cycle 1 Day 8 onwards. Each cycle is 28 days.
All Cause Mortality
	Carfilzomib
	Affected / at Risk (%)	# Events
Total	0/13 (0%)
Serious Adverse Events
	Carfilzomib
	Affected / at Risk (%)	# Events
Total	3/13 (23.1%)
Blood and lymphatic system disorders
Acute Pulmonary Embolism	1/13 (7.7%)
Musculoskeletal and connective tissue disorders
Leg pain	1/13 (7.7%)
Respiratory, thoracic and mediastinal disorders
Pneumonia	1/13 (7.7%)
Other (Not Including Serious) Adverse Events
	Carfilzomib
	Affected / at Risk (%)	# Events
Total	13/13 (100%)
Blood and lymphatic system disorders
anemia	8/13 (61.5%)	33
lower extremity edema	1/13 (7.7%)	1
leukocyte count decreased	3/13 (23.1%)	3
lymphocyte count decreased	3/13 (23.1%)	18
lymphopenia	1/13 (7.7%)	1
neutrophil count decreased	4/13 (30.8%)	38
platelet count decreased	7/13 (53.8%)	29
swelling in lower ankles	1/13 (7.7%)	1
Cardiac disorders
ejection fraction drop	2/13 (15.4%)	2
hypertension	7/13 (53.8%)	22
hypertension chronic and intermittent fluctuation	1/13 (7.7%)	1
hypotension	1/13 (7.7%)	1
white blood cell decrease	1/13 (7.7%)	1
Gastrointestinal disorders
constipation	4/13 (30.8%)	4
dyspepsia	1/13 (7.7%)	1
gastroesophageal reflux disease	1/13 (7.7%)	1
General disorders
anorexia	1/13 (7.7%)	1
chest heaviness	1/13 (7.7%)	1
diaphoresis	1/13 (7.7%)	1
dizziness	1/13 (7.7%)	1
epigastric pain	1/13 (7.7%)	1
Fatigue	3/13 (23.1%)	3
Fever	3/13 (23.1%)	4
high blood pressure	1/13 (7.7%)	1
malaise	1/13 (7.7%)	1
nausea	2/13 (15.4%)	5
pain	3/13 (23.1%)	3
left mandible pain	1/13 (7.7%)	1
shakiness/weakness	1/13 (7.7%)	1
sinusitis	1/13 (7.7%)	1
vomiting	1/13 (7.7%)	3
weight loss	1/13 (7.7%)	1
Infections and infestations
cellulitis	1/13 (7.7%)	1
yeast infection	1/13 (7.7%)	1
Metabolism and nutrition disorders
alanine aminotransferase increased	1/13 (7.7%)	1
alkaline phosphatase increased	1/13 (7.7%)	2
ankle swelling	1/13 (7.7%)	1
asparate aminotransferase increased	3/13 (23.1%)	3
Elevated bilirubin	1/13 (7.7%)	1
elevated GGT	1/13 (7.7%)	1
hypercalcemia	6/13 (46.2%)	6
hyperglycemia	1/13 (7.7%)	1
hyperkalemia	2/13 (15.4%)	3
hypernatremia	1/13 (7.7%)	1
hyperphostphatemia	3/13 (23.1%)	4
hypokalemia	1/13 (7.7%)	1
Musculoskeletal and connective tissue disorders
anterolisthesis of L5 over S1	1/13 (7.7%)	1
bilateral lower extremity leg pain	1/13 (7.7%)	2
back pain	1/13 (7.7%)	1
bilateral hip pain	1/13 (7.7%)	1
bone pain	1/13 (7.7%)	1
intermittent sternal pain	1/13 (7.7%)	1
joint pain	1/13 (7.7%)	1
left rib pain	1/13 (7.7%)	1
left thigh pain	1/13 (7.7%)	1
minor cramps	1/13 (7.7%)	1
right iliac bone pain	1/13 (7.7%)	1
right rib pain	2/13 (15.4%)	3
Nervous system disorders
drift when walking	1/13 (7.7%)	1
hallucinations	1/13 (7.7%)	1
Headache	6/13 (46.2%)	19
neuropathy	1/13 (7.7%)	1
seizure	1/13 (7.7%)	1
Renal and urinary disorders
Acute kidney injury	1/13 (7.7%)	1
Acute renal failure	1/13 (7.7%)	1
creatinine elevated	4/13 (30.8%)	4
decreased creatinine clearance	1/13 (7.7%)	1
Reproductive system and breast disorders
vaginal pain	1/13 (7.7%)	1
Respiratory, thoracic and mediastinal disorders
Acute dyspnea	1/13 (7.7%)	1
chest pain	2/13 (15.4%)	4
cough	3/13 (23.1%)	3
non productive cough	1/13 (7.7%)	1
pneumonitis	1/13 (7.7%)	1
shortness of breath	1/13 (7.7%)	2
upper respiratory infection	3/13 (23.1%)	3
wheezing	1/13 (7.7%)	1
Skin and subcutaneous tissue disorders
pruritic reddish hands with pain on hands wrist and arms	1/13 (7.7%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE 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.