Clofarabine for Relapsed or Refractory T-Cell or B-Cell Non-Hodgkin Lymphoma (NHL)

• Sponsor: Oncology Specialists, S.C. (Other)
• Overall Status: Completed
• CT.gov ID: NCT00156013
• Collaborator: Genzyme, a Sanofi Company (Industry)
• Enrollment: 33
• Location: 1
• Arm: 1
• Duration (Months): 55
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

This research is being done to develop new treatment for non-hodgkin's lymphoma in subjects whose cancer has returned or resisted treatment with chemotherapy. The investigational drug clofarabine is being used in this study. An investigational drug is one that has not been approved by the United States Food and Drug Administration (FDA).

Condition or Disease	Intervention/Treatment	Phase
Lymphoma, B-Cell; Lymphoma, Non-Hodgkin	Drug: CLOFARABINE	Phase 1/Phase 2

Detailed Description

The safety profile of clofarabine appears acceptable within the target populations studied to date in the clinical studies, with numerous responses observed in heavily pre-treated patients with relapsed/refractory ALL or AML. Dose escalation of clofarabine in patients with solid tumors and lymphoproliferative disorders has been limited because grade 3 and 4 myelosuppression was considered acceptable in patients with acute leukemia, provided that hematologic recovery occurred within 6 weeks of therapy , and dose escalation has proceeded as high as 40 mg/m2 in this patient population. Furthermore, no responses were observed in a recent trial in which patients with relapsed CLL were treated with clofarabine 2 mg/m2, an indolent B-cell lymphoproliferative disorder indicating that low doses are likely to be ineffective in patients with aggressive NHL. (Personal Communication with ILEX Products, INC.)

This Phase I/II study will evaluate escalating doses of clofarabine in patients with relapsed and refractory diffuse large cell B-cell NHL starting at a dose of 4 mg/m2/day for 5 consecutive days and repeated every 28 days for a maximum of 6 cycles. This dosing regimen should be evaluated in this patient population because there is no standard therapy at relapse and grade 3 and 4 myelosuppression is frequently observed with traditional NHL salvage. Additionally, patients will receive granulocyte colony stimulating factors at the discretion of the investigator. Antifungal and antibacterial prophylaxis will be administered to minimize the risk of infection.

Study Design

• Study Type: Interventional
• Actual Enrollment: 33 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I/II Open-label Study of Clofarabine in Patients With Relapsed or Refractory Diffuse Large Cell B-Cell NHL
• Study Start Date: Sep 1, 2005
• Actual Primary Completion Date: Apr 1, 2010
• Actual Study Completion Date: Apr 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 1 Clofarabine 4 mg/m^2 days 1-5 of every cycle for a maximum of 6 cycles.	Drug: CLOFARABINE; 4 mg/m^2 days 1-5 of every cycle for a maximum of 6 cycles; Other Names: Clolar®

Outcome Measures

Primary Outcome Measures

1. Phase I Maximum Tolerated Dose [days 1 -28, maximum 6 cycles]

   Maximum Tolerated Dose for Clofarabine. Cohorts of 3 patients each will receive doses of clofarabine increased in increments as follows: 4, 6, 8, 10, 12,…etc mg/m2/day for 5 days. The dose level immediately below the MTD will be used to treat patients in the Phase II part of the study. Starting dose of 4 mg/m2.

2. Phase II Overall Response [5 years]

   Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.

Secondary Outcome Measures

1. Toxicity [5 years]

   Number of Participants with Toxicity

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Adult patients who are at least 18 years old with histology confirmed diffuse large cell B-cell NHL who have failed prior systemic chemotherapy with or without monoclonal antibody-based therapies.

• Measurable disease determined by Ct or PET scans or bone marrow involvement, defined as lesions that can be accurately measured in two dimensions by CT or PET scan with the longest diameter accurately as greater than or equal to 1.0 cm or palpable lesions with both diameters greater than or equal to 2.0 cm. PET scan measurable disease is defined based on SUV value as determined by nuclear medicine evaluation.

• Eastern Cooperative Oncology Group (ECOG) performance status of 0,1,or 2.

• Life expectancy greater than 12 weeks.

• Laboratory values obtained less than or equal to 14 days prior to registration:

• Absolute neutrophil count (ANC) greater than or equal to 1500.

• White blood cell (WBC) count greater than 3.0.

• Platelets greater than or equal to 100.

• Hemoglobin (HG) greater than 9.0 g/dL.

• Total bilirubin less than or equal to 2.0 mg/dL.

• Aspartate transaminase (AST)/alanine transaminase (ALT) less than or equal to 3 times the upper limit of normal (ULN). Higher values are acceptable if it is deemed that they are related to liver involvement with NHL.

• Serum creatinine less than or equal to 2.0 mg/dL.

• Cardiac function on pretreatment MUGA scan or echocardiogram that is considered normal by institutional standards.

• Capable of understanding the investigational nature, potential risks and benefits of the study, and able to provide valid informed consent.

• Female patients of childbearing potential must have a negative serum pregnancy test within 2 weeks prior to enrollment.

• Male and female patients must use an effective contraceptive method during the study and for a minium of 6 months after study treatment.

Exclusion Criteria:

• Previously untreated NHL.

• Received previous treatment with clofarabine.

• History of T-cell lymphoma.

• Bulky disease (ie, any single mass greater than 10 cm or circulating malignant cells greater than or equal to 24,000 cells/ul.

• Patients with known AIDS-related or HIV-positive lymphoma.

• Autologous bone marrow or stem cell transplant within 3 months of study entry.

• History of allogeneic bone marrow transplant or organ transplant.

• Prior radiotherapy to the only site of measurable disease.

• Any medical condition that requires chronic use of oral high-dose corticosteroids. ( in excess of 1 mg/kg/day).

• Autoimmune thrombocytopenia.

• Use if investigational agents within 30 days or any anticancer therapy within 3 weeks before study entry. The patient must have recovered from all acute toxicities from any previous therapy.

• Patients with an active, uncontrolled systemic infection considered to be opportunistic, life threatening, or clinically significant at the time of treatment or with a known or suspected fungal infection (ie, patients of parenteral antifungal therapy).

• HIV-positive status.

• Active secondary malignancy.

• Pregnant or lactating patients.

• Any significant concurrent disease, illness , or psychiatric disorder that would compromise patient safety or compliance, interfere with consent, study participation, follow-up, or interpretation of study results.

• Patients with active or untreated central nervous lymphoma (CNS) lymphoma.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Oncology Specialists, SC	Park Ridge	Illinois	United States	60068

Sponsors and Collaborators

• Oncology Specialists, S.C.
• Genzyme, a Sanofi Company

Investigators

• Principal Investigator: Chadi Nabhan, MD, Oncology Specialists,SC

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Dr. Sigrun Hallmeyer, Principal Investigator, Oncology Specialists, S.C.
• ClinicalTrials.gov Identifier: NCT00156013
• Other Study ID Numbers: 1066306 (0408); NCT00305721
• First Posted: Sep 12, 2005
• Last Update Posted: Nov 29, 2017
• Last Verified: Oct 1, 2017

• Keywords provided by Dr. Sigrun Hallmeyer, Principal Investigator, Oncology Specialists, S.C.: B-Cell NHL
• Additional relevant MeSH terms: Lymphoma; Lymphoma, Non-Hodgkin; Lymphoma, B-Cell; Clofarabine

Study Results

Participant Flow

Arm/Group Title	Clofarabine
Arm/Group Description	Clofarabine 4 mg/m^2 days 1-5 of every cycle for a maximum of 6 cycles.
Period Title: Overall Study
STARTED	33
COMPLETED	31
NOT COMPLETED	2

Baseline Characteristics

Arm/Group Title	Clofarabine
Arm/Group Description	Clofarabine 4 mg/m^2 days 1-5 of every cycle for a maximum of 6 cycles.
Overall Participants	33
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	13 39.4%
>=65 years	20 60.6%
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	69
Sex: Female, Male (Count of Participants)
Female	19 57.6%
Male	14 42.4%
Region of Enrollment (participants) [Number]
United States	33 100%

Outcome Measures

1. Primary Outcome

Title	Phase I Maximum Tolerated Dose
Description	Maximum Tolerated Dose for Clofarabine. Cohorts of 3 patients each will receive doses of clofarabine increased in increments as follows: 4, 6, 8, 10, 12,…etc mg/m2/day for 5 days. The dose level immediately below the MTD will be used to treat patients in the Phase II part of the study. Starting dose of 4 mg/m2.
Time Frame	days 1 -28, maximum 6 cycles

Outcome Measure Data

Analysis Population Description

Per protocol guidelines for accrual to the cohorts.

Arm/Group Title	Clofarabine
Arm/Group Description	During the Phase I part of the study, the starting dose of clofarabine will be 4 mg/m2 administered by IVI over 1 hour for 5 consecutive days and repeated every 28 days until disease progression is observed or for a maximum of 6 cycles. Cohorts of 3 patients each will receive doses of clofarabine increased in increments of 2mg/m2. The MTD was 6mg/m2. The dose level immediately below the MTD (4mg/m2) will be used to treat patients in the Phase II part of the study.
Measure Participants	33
Number [mg/m^2]	6

2. Primary Outcome

Title	Phase II Overall Response
Description	Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
Time Frame	5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Open Label Trial of Clofarabine in Relapsed or Refractory NHL
Arm/Group Description	Clofarabine 4 mg/m^2 days 1-5 of every cycle for a maximum of 6 cycles. CLOFARABINE: 4 mg/m^2 days 1-5 of every cycle for a maximum of 6 cycles
Measure Participants	33
patients achieving a complete response	7 21.2%
patients achieving a partial response	6 18.2%
Patients not achieving a response	20 60.6%

3. Secondary Outcome

Title	Toxicity
Description	Number of Participants with Toxicity
Time Frame	5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Toxicity
Arm/Group Description	Myelosuppresion
Measure Participants	33
grade 3 or higher neutropenia or thrombocytopenia	20 60.6%
neutropenia or thrombocytopenia less than grade 2	13 39.4%

Adverse Events

Arm/Group Title	Clofarabine
Arm/Group Description	Clofarabine 4 mg/m^2 days 1-5 of every cycle for a maximum of 6 cycles.
All Cause Mortality
	Clofarabine
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Clofarabine
	Affected / at Risk (%)	# Events
Total	21/33 (63.6%)
Blood and lymphatic system disorders
Anemia	1/33 (3%)	1
hypokalemia	1/33 (3%)	1
pancytopenia	3/33 (9.1%)	3
thrombocytopenia	2/33 (6.1%)	2
Cardiac disorders
Atrial fibrillation	2/33 (6.1%)	2
syncope	1/33 (3%)	1
Endocrine disorders
hyperglycemia	1/33 (3%)	1
Infections and infestations
bilateral lower extremity celluiltis	1/33 (3%)	1
fever of unknown origin	1/33 (3%)	1
neutropenic fever	6/33 (18.2%)	6
Musculoskeletal and connective tissue disorders
arthralgia	1/33 (3%)	1
lower back pain	1/33 (3%)	1
abdominal pain	1/33 (3%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
tumor lysis syndrome	2/33 (6.1%)	2
Nervous system disorders
seizure	1/33 (3%)	1
Psychiatric disorders
mental status changes	1/33 (3%)	1
Renal and urinary disorders
renal failure	1/33 (3%)	1
renal insufficiency	1/33 (3%)	1
Respiratory, thoracic and mediastinal disorders
pleural effusion	1/33 (3%)	1
pneumonia	1/33 (3%)	1
pulmonary edema	1/33 (3%)	1
Other (Not Including Serious) Adverse Events
	Clofarabine
	Affected / at Risk (%)	# Events
Total	33/33 (100%)
Blood and lymphatic system disorders
Alk Phos	6/33 (18.2%)	6
anemia	27/33 (81.8%)	27
bilateral lower extremity erythema & swelling	1/33 (3%)	1
bruising on forearms	1/33 (3%)	1
creatinine	7/33 (21.2%)	7
decreased leukocytes	1/33 (3%)	1
edema	5/33 (15.2%)	5
elevated albumin	1/33 (3%)	1
elevated ANC	1/33 (3%)	1
elevated AST/ALT	1/33 (3%)	1
granulcytopenia	1/33 (3%)	1
hypernatremia	1/33 (3%)	1
hypokalemia	4/33 (12.1%)	4
hypocalcemia	1/33 (3%)	1
hypomagnsmia	1/33 (3%)	1
hypophosphatemia	1/33 (3%)	1
hyponatremia	1/33 (3%)	1
hypovolemia	1/33 (3%)	1
leukopenia	14/33 (42.4%)	14
low albumin	2/33 (6.1%)	2
low magnesium	2/33 (6.1%)	2
low phosphorus	1/33 (3%)	1
lymphopenia	1/33 (3%)	1
neutropenia	28/33 (84.8%)	28
SGOT	2/33 (6.1%)	2
SGPT	4/33 (12.1%)	4
bilirubin	2/33 (6.1%)	2
thrombocytopenia	33/33 (100%)	33
Cardiac disorders
angina	1/33 (3%)	1
hypertension	1/33 (3%)	1
hypotension	4/33 (12.1%)	4
orthostatic hypotension	1/33 (3%)	1
palpitations	1/33 (3%)	1
systoloc ejection murmur	1/33 (3%)	1
tachycardia	3/33 (9.1%)	3
Ear and labyrinth disorders
difficulty hearing	1/33 (3%)	1
ear pain	1/33 (3%)	1
Endocrine disorders
hyperglycemia	14/33 (42.4%)	14
Eye disorders
dry eyes	1/33 (3%)	1
Gastrointestinal disorders
constipation	6/33 (18.2%)	6
decreased appetite	5/33 (15.2%)	5
dehydration	1/33 (3%)	1
diarrhea	3/33 (9.1%)	3
dry mouth	1/33 (3%)	1
dysphagia	2/33 (6.1%)	2
heartburn	2/33 (6.1%)	2
hypoalbuminemia	2/33 (6.1%)	2
mucositis	1/33 (3%)	1
nausea	16/33 (48.5%)	16
paralytic ileus	1/33 (3%)	1
pharyngitis	1/33 (3%)	1
vomiting	10/33 (30.3%)	10
General disorders
alopecia	3/33 (9.1%)	3
anion gap acidosis	1/33 (3%)	1
anorexia	2/33 (6.1%)	2
arm swelling	1/33 (3%)	1
decreased performance status	1/33 (3%)	1
fatigue	14/33 (42.4%)	14
gingivitis	1/33 (3%)	1
ingrown toenail	1/33 (3%)	1
chills	1/33 (3%)	1
malaise	1/33 (3%)	1
night sweats	2/33 (6.1%)	2
weakness	5/33 (15.2%)	5
weight gain	1/33 (3%)	1
weight loss	1/33 (3%)	1
pain	7/33 (21.2%)	7
Infections and infestations
bacteremia	1/33 (3%)	1
febrile neutropenia	1/33 (3%)	1
fever	4/33 (12.1%)	4
infection	2/33 (6.1%)	2
Metabolism and nutrition disorders
protein calorie malnutrition	1/33 (3%)	1
protein low	1/33 (3%)	1
Musculoskeletal and connective tissue disorders
abdominal bloating	1/33 (3%)	1
abdominal girth	1/33 (3%)	1
abdominal pain	2/33 (6.1%)	2
ankle pain	1/33 (3%)	1
back pain	1/33 (3%)	1
bilateral leg cramping and hand cramping	2/33 (6.1%)	2
chest pain	1/33 (3%)	1
joint pain	5/33 (15.2%)	5
Nervous system disorders
delirium	1/33 (3%)	1
dizziness	5/33 (15.2%)	5
headache	2/33 (6.1%)	2
neuropathy	1/33 (3%)	1
Psychiatric disorders
anxiety	1/33 (3%)	1
depression	3/33 (9.1%)	3
Renal and urinary disorders
acute renal failure	1/33 (3%)	1
decreased renal perfusion	1/33 (3%)	1
hydronephrosis	1/33 (3%)	1
renal artery vasoconstruction	1/33 (3%)	1
Respiratory, thoracic and mediastinal disorders
cough	5/33 (15.2%)	5
dyspnea	5/33 (15.2%)	5
nasal congestion	2/33 (6.1%)	2
dry cough	1/33 (3%)	1
right pleural effusion	3/33 (9.1%)	3
runny nose	2/33 (6.1%)	2
shortness of breath	5/33 (15.2%)	5
sinus problems	2/33 (6.1%)	2
upper respiratory infection	2/33 (6.1%)	2
wheezing	3/33 (9.1%)	3
Skin and subcutaneous tissue disorders
dry skin	1/33 (3%)	1
itching	2/33 (6.1%)	2
pruritis	1/33 (3%)	1
rash	3/33 (9.1%)	3

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.