Combination Veltuzumab and Fractionated 90Y- Epratuzumab Radioimmunotherapy in Follicular Lymphoma

• Sponsor: Weill Medical College of Cornell University (Other)
• Overall Status: Terminated
• CT.gov ID: NCT01147393
• Collaborator: Gilead Sciences (Industry)
• Enrollment: 4
• Location: 1
• Arm: 1
• Actual Duration (Months): 58
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

A Phase I/II clinical trial using a fractionated dosing regimen of 90Y-epratuzumab (anti-CD22) has showed encouraging responses in follicular and aggressive NHL with an ability to administer safely 2 injections of 20 mCi/m2 spaced 1 week apart. The investigators propose to combine this active 90Y-epratuzumab treatment with a regimen of veltuzumab that was also found active in Phase I/II trials.

The goal of this study is to determine the safety and efficacy of 90Y-epratuzumab when used in combination with veltuzumab. The primary objective is to determine the response rate of this combination treatment. Secondary objectives are to assess safety, pharmacokinetics and targeting of 90Y-epratuzumab . Veltuzumab blood levels and anti-antibody responses will also be monitored at various times.

Condition or Disease	Intervention/Treatment	Phase
Follicular Lymphoma	Drug: 90Y-epratuzumab tetraxetan; Biological: veltuzumab	Phase 1/Phase 2

Detailed Description

The treatment regimen consists of 2 elements. The first element is represented by one courses of veltuzumab (4 weekly injections of 200 mg/m2). 90Y-epratuzumab will be given as 2 injections at escalating doses 1 week apart and administered starting one week following the 4th veltuzumab injection.

After confirming eligibility and undergoing baseline assessments, the treatment starts with an imaging study using 111In-epratuzumab (5-mCi 111In-DOTA-epratuzumab co-infused with a total of 1.5 mg/kg unlabeled epratuzumab). Blood samples (~7 samples, 5 mL each) for pharmacokinetic analysis will be collected over 5-7 days, and patients will be imaged on 4 separate occasions (e.g., the day of injection (Day 0), Day 1, Day 3, 4, or 5, and day 6 or 7).

The patient will then initiate veltuzumab treatments starting 7 days after the 111In-epratuzumab injection. Veltuzumab is given in 4 weekly doses, each 200 mg/m2. A single blood sample will be taken before each veltuzumab dose to assess residual veltuzumab concentrations in the serum, and then at 1 h later to determine peak values. Patients will receive unlabeled, unconjugated epratuzumab (1.5 mg/kg) that will be infused over ~30 minutes. Patients will also receive 111In-epratuzumab immediately following the unlabeled epratuzumab. Blood samples will be collected at the same intervals as after the first 111In-epratuzumab. Only 2 imaging sessions will be required, on Day 1 and then again on day 6 or 7 (these days should match those obtained after the first 111In-epratuzumab injection).

The 90Y-epratuzumab treatment will begin one week after the 4th veltuzumab injection. Patients will receive unlabeled, unconjugated epratuzumab (1.5 mg/kg) that will be infused over ~30 minutes. All patients will then receive a 90Y-epratuzumab dose. Dose will be escalated by patient cohort starting at 2x15 mCi/m2 and, at 2x 20 mCi/m2, and 2x 25 mCi/m2.. Blood samples will be collected at the same intervals as after each 111In-epratuzumab.Patients will also receive 111In-epratuzumab immediately following the unlabeled epratuzumab and immediately before the 90Y-epratuzumab injection. Blood samples will be collected at the same intervals as after the first 111In-epratuzumab. Only 2 imaging sessions will be required, on Day 1 and then again on day 6 or 7 (these days should match those obtained after the first 111In-epratuzumab injection).

The second 90Y-epratuzumab treatment will be given at the same dose, 1 week after the first 90Y-epratuzumab dose. CBC will be checked prior to administration of this second dose to ensure blood counts continue to meet criteria for treatment as specified in inclusion criteria. Blood samples will again be collected over the same period as the first injection, but no imaging studies are required.

Patients are closely monitored during all infusions, and then at intervals over a 12-weeks post-treatment evaluation period, with evaluation procedures including vital signs, physical examination, CT (chest, abdomen, pelvis, other regions of involvement), CBC, serum chemistries, serum immunoglobulins, urinalysis, peripheral blood B-cell levels (immunophenotyping based on CD19), and serum samples for HAHA (veltuzumab and epratuzumab ELISA to be analyzed by Immunomedics). Follow-up evaluations then continue every 3 months for up to 5 years or until progression occurs or until resolution of treatment-related toxicity.

Study Design

• Study Type: Interventional
• Actual Enrollment: 4 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase I/II Study of Combination Veltuzumab (Anti-CD20) and Fractionated 90Y- Epratuzumab (Anti-CD22) Radioimmunotherapy in Patients With Follicular Lymphoma
• Actual Study Start Date: Oct 1, 2010
• Actual Primary Completion Date: Aug 6, 2013
• Actual Study Completion Date: Jul 31, 2015

Arms and Interventions

Arm

Intervention/Treatment

Experimental: All subjects two weekly infusions of 90Y-epratuzumab tetraxetan in combination with four weekly infusions of 200 mg/m2 veltuzumab.

Drug: 90Y-epratuzumab tetraxetan; The 90Y-epratuzumab treatment will begin one week after the 4th veltuzumab injection. Patients will receive unlabeled, unconjugated epratuzumab (1.5 mg/kg) that will be infused over ~30 minutes. All patients will then receive a 90Y-epratuzumab dose. Dose will be escalated by patient cohort either at 15 mCi/m2 or 20 mCi/m2. The second 90Y-epratuzumab treatment will be given at the same dose, 1 week after the first 90Y-epratuzumab dose.; Biological: veltuzumab; Veltuzumab is given in 4 weekly doses, each 200 mg/m2.

Outcome Measures

Primary Outcome Measures

1. Determine the Maximum Tolerated 90Y Dose []

2. Dose-limiting Toxicity []

   NCI CTC version 3.0 is used to grade all adverse events and to provide management guidelines for infusional toxicity. Dose-limiting toxicity (DLT) is defined as follows: Hematologic: Grade 4 toxicity >7 days, as specified by hemoglobin levels, platelet counts or absolute neutrophil count (ANC) or failure of hemoglobin levels, platelet counts or ANC to recover to Grade 1 levels within 12 weeks of completing the treatment cycle (with the use of RBC and platelet transfusions or growth factors during the 12 weeks if necessary, but at least one week without any support prior to qualifying Grade 1 levels). Non-Hematologic: Any Grade 3 or Grade 4. Other: Any Grade 2 autoimmune reactions, or the occurrence of Grade 2 immediate-type allergic/hypersensitivity reactions (e.g., urticaria, wheezing, hypoxia and dyspnea) will be considered DLT and will also require the infusion to be permanently terminated. Occurrence of DLT requires a patient's treatment to be permanently discontinued

3. Safety []

4. The Primary Objective of the Phase II Portion of the Study is to Determine the Anti-tumor Efficacy, as Measured by Response Rate, of Fractionated 90Y-epratutumab IgG Given in Combination With Veltuzumab Anti-CD20 IgG Therapy []

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Male or female, >18 years old

• Histological diagnosis of CD20+ Follicular lymphoma by WHO lymphoma criteria.

• FLIPI intermediate or high risk (2-5 risk factors)

• No prior systemic treatment for NHL

• Measurable disease by CT, with at least one lesion >1.5 cm in one dimension

• Life expectancy of at least 6 months

• ECOG performance status > = 2

• Patients must have normal organ and marrow function as defined below:

• ANC > = 1,500/uL

• platelets > = 100,000/uL

• total bilirubin < = 1.5 x upper limit of normal

• AST(SGOT)/ALT(SGPT) < = 2.5 X upper limit of normal

• creatinine < = 1.5 x upper limit of normal

• Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

• Pregnant or lactating women. Women of childbearing potential are required to have a negative pregnancy test

• Women of childbearing potential and fertile men who are not practicing or who are unwilling to practice birth control while enrolled in the study until at least 12 weeks after the last weekly veltuzumab infusion.

• Primary CNS lymphoma, HIV lymphoma or transformed lymphoma, or presence of symptomatic CNS metastases or carcinomatous meningitis.

• Bulky disease by CT, defined as any single mass >10 cm in its greatest diameter

• Disease status eligible for potentially curative external beam radiation (stage 1 or contiguous stage 2 at sites appropriate for radiotherapy)

• Bone marrow involvement ≥25%; patients with CLL

• Pleural effusion with positive cytology for lymphoma

• Patients known to be HIV positive or hepatitis B positive

• Corticosteroid use within 2 weeks, unless 20 mg/day or less at stable dose.

• Prior malignancy with less than a 1-year disease-free interval, excluding non-melanoma skin cancers and carcinoma in situ of the cervix.

• Other concurrent medical or psychiatric conditions that, in the Investigator's opinion, may be likely to confound study interpretation or prevent completion of study procedures and follow-up examinations

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Weill Cornell Medical College	New York	New York	United States	10065

Sponsors and Collaborators

• Weill Medical College of Cornell University
• Gilead Sciences

Investigators

• Principal Investigator: Peter Martin, MD, Weill Medical College of Cornell University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Weill Medical College of Cornell University
• ClinicalTrials.gov Identifier: NCT01147393
• Other Study ID Numbers: 1001010838
• First Posted: Jun 22, 2010
• Last Update Posted: Feb 22, 2018
• Last Verified: Jan 1, 2018

• Additional relevant MeSH terms: Lymphoma; Lymphoma, Follicular; Epratuzumab; Veltuzumab; 1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid

Study Results

Participant Flow

Arm/Group Title	All Subjects
Arm/Group Description	two weekly infusions of 90Y-epratuzumab tetraxetan in combination with four weekly infusions of 200 mg/m2 veltuzumab. 90Y-epratuzumab tetraxetan: The 90Y-epratuzumab treatment will begin one week after the 4th veltuzumab injection. Patients will receive unlabeled, unconjugated epratuzumab (1.5 mg/kg) that will be infused over ~30 minutes. All patients will then receive a 90Y-epratuzumab dose. Dose will be escalated by patient cohort either at 15 mCi/m2 or 20 mCi/m2. The second 90Y-epratuzumab treatment will be given at the same dose, 1 week after the first 90Y-epratuzumab dose. veltuzumab: Veltuzumab is given in 4 weekly doses, each 200 mg/m2.
Period Title: Dose Level 1
STARTED	3
COMPLETED	1
NOT COMPLETED	2
Period Title: Dose Level 1
STARTED	1
COMPLETED	0
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	All Subjects
Arm/Group Description	two weekly infusions of 90Y-epratuzumab tetraxetan in combination with four weekly infusions of 200 mg/m2 veltuzumab. 90Y-epratuzumab tetraxetan: The 90Y-epratuzumab treatment will begin one week after the 4th veltuzumab injection. Patients will receive unlabeled, unconjugated epratuzumab (1.5 mg/kg) that will be infused over ~30 minutes. All patients will then receive a 90Y-epratuzumab dose. Dose will be escalated by patient cohort either at 15 mCi/m2 or 20 mCi/m2. The second 90Y-epratuzumab treatment will be given at the same dose, 1 week after the first 90Y-epratuzumab dose. veltuzumab: Veltuzumab is given in 4 weekly doses, each 200 mg/m2.
Overall Participants	4
Age, Customized (Count of Participants)
60-69 Years of Age	3 75%
70-79 Years of Age	1 25%
Sex: Female, Male (Count of Participants)
Female	3 75%
Male	1 25%

Outcome Measures

1. Primary Outcome

Title	Determine the Maximum Tolerated 90Y Dose

Outcome Measure Data

Analysis Population Description

Data was not collected

Arm/Group Title	All Subjects
Arm/Group Description	two weekly infusions of 90Y-epratuzumab tetraxetan in combination with four weekly infusions of 200 mg/m2 veltuzumab. 90Y-epratuzumab tetraxetan: The 90Y-epratuzumab treatment will begin one week after the 4th veltuzumab injection. Patients will receive unlabeled, unconjugated epratuzumab (1.5 mg/kg) that will be infused over ~30 minutes. All patients will then receive a 90Y-epratuzumab dose. Dose will be escalated by patient cohort either at 15 mCi/m2 or 20 mCi/m2. The second 90Y-epratuzumab treatment will be given at the same dose, 1 week after the first 90Y-epratuzumab dose. veltuzumab: Veltuzumab is given in 4 weekly doses, each 200 mg/m2.
Measure Participants	0

2. Primary Outcome

Title

Dose-limiting Toxicity

Description

NCI CTC version 3.0 is used to grade all adverse events and to provide management guidelines for infusional toxicity. Dose-limiting toxicity (DLT) is defined as follows: Hematologic: Grade 4 toxicity >7 days, as specified by hemoglobin levels, platelet counts or absolute neutrophil count (ANC) or failure of hemoglobin levels, platelet counts or ANC to recover to Grade 1 levels within 12 weeks of completing the treatment cycle (with the use of RBC and platelet transfusions or growth factors during the 12 weeks if necessary, but at least one week without any support prior to qualifying Grade 1 levels). Non-Hematologic: Any Grade 3 or Grade 4. Other: Any Grade 2 autoimmune reactions, or the occurrence of Grade 2 immediate-type allergic/hypersensitivity reactions (e.g., urticaria, wheezing, hypoxia and dyspnea) will be considered DLT and will also require the infusion to be permanently terminated. Occurrence of DLT requires a patient's treatment to be permanently discontinued

Outcome Measure Data

Analysis Population Description

Data were not collected

Arm/Group Title	All Subjects
Arm/Group Description	two weekly infusions of 90Y-epratuzumab tetraxetan in combination with four weekly infusions of 200 mg/m2 veltuzumab. 90Y-epratuzumab tetraxetan: The 90Y-epratuzumab treatment will begin one week after the 4th veltuzumab injection. Patients will receive unlabeled, unconjugated epratuzumab (1.5 mg/kg) that will be infused over ~30 minutes. All patients will then receive a 90Y-epratuzumab dose. Dose will be escalated by patient cohort either at 15 mCi/m2 or 20 mCi/m2. The second 90Y-epratuzumab treatment will be given at the same dose, 1 week after the first 90Y-epratuzumab dose. veltuzumab: Veltuzumab is given in 4 weekly doses, each 200 mg/m2.
Measure Participants	0

3. Primary Outcome

Title	Safety

Outcome Measure Data

Analysis Population Description

Data was not evaluated

Arm/Group Title	All Subjects
Arm/Group Description	two weekly infusions of 90Y-epratuzumab tetraxetan in combination with four weekly infusions of 200 mg/m2 veltuzumab. 90Y-epratuzumab tetraxetan: The 90Y-epratuzumab treatment will begin one week after the 4th veltuzumab injection. Patients will receive unlabeled, unconjugated epratuzumab (1.5 mg/kg) that will be infused over ~30 minutes. All patients will then receive a 90Y-epratuzumab dose. Dose will be escalated by patient cohort either at 15 mCi/m2 or 20 mCi/m2. The second 90Y-epratuzumab treatment will be given at the same dose, 1 week after the first 90Y-epratuzumab dose. veltuzumab: Veltuzumab is given in 4 weekly doses, each 200 mg/m2.
Measure Participants	0

4. Primary Outcome

Title	The Primary Objective of the Phase II Portion of the Study is to Determine the Anti-tumor Efficacy, as Measured by Response Rate, of Fractionated 90Y-epratutumab IgG Given in Combination With Veltuzumab Anti-CD20 IgG Therapy

Outcome Measure Data

Analysis Population Description

Data were not collected

Arm/Group Title	All Subjects
Arm/Group Description	two weekly infusions of 90Y-epratuzumab tetraxetan in combination with four weekly infusions of 200 mg/m2 veltuzumab. 90Y-epratuzumab tetraxetan: The 90Y-epratuzumab treatment will begin one week after the 4th veltuzumab injection. Patients will receive unlabeled, unconjugated epratuzumab (1.5 mg/kg) that will be infused over ~30 minutes. All patients will then receive a 90Y-epratuzumab dose. Dose will be escalated by patient cohort either at 15 mCi/m2 or 20 mCi/m2. The second 90Y-epratuzumab treatment will be given at the same dose, 1 week after the first 90Y-epratuzumab dose. veltuzumab: Veltuzumab is given in 4 weekly doses, each 200 mg/m2.
Measure Participants	0

Adverse Events

Arm/Group Title	Dose Level 1		Dose Level -1
Arm/Group Description	veltzumab: 200 mg/m2 Unconjugated epratuzumab: 1.5 mg/kg 111-In-epratuzumab: 5 mCi 90-Y-epratuzumab: 15 mCi/m2		veltzumab: 200 mg/m2 Unconjugated epratuzumab: 1.5 mg/kg 111-In-epratuzumab: 5 mCi 90-Y-epratuzumab: 10 mCi/m2
All Cause Mortality
	Dose Level 1		Dose Level -1
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Dose Level 1		Dose Level -1
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/3 (0%)		0/1 (0%)
Other (Not Including Serious) Adverse Events
	Dose Level 1		Dose Level -1
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/3 (100%)		1/1 (100%)
Blood and lymphatic system disorders
Neutropenia	3/3 (100%)	5	1/1 (100%)	3
Lymphopenia	3/3 (100%)	5	1/1 (100%)	1
Leukopenia	3/3 (100%)	5	0/1 (0%)	0
Thrombocytopenia	1/3 (33.3%)	6	1/1 (100%)	2
Anemia	1/3 (33.3%)	1	1/1 (100%)	1
Easy bruisability	1/3 (33.3%)	1	0/1 (0%)	0
Eye disorders
Vision blurred	1/3 (33.3%)	1	0/1 (0%)	0
General disorders
Fatigue	1/3 (33.3%)	1	1/1 (100%)	1
Flutters (neck and throat)	1/3 (33.3%)	1	0/1 (0%)	0
Taste alteration	1/3 (33.3%)	1	0/1 (0%)	0
Bleeding gums	1/3 (33.3%)	1	0/1 (0%)	0
Nasal congestion	1/3 (33.3%)	1	0/1 (0%)	0
Cough	1/3 (33.3%)	1	0/1 (0%)	0
Epistaxis	1/3 (33.3%)	1	0/1 (0%)	0
Dyspnea	2/3 (66.7%)	3	1/1 (100%)	1
Insomnia	3/3 (100%)	4	0/1 (0%)	0
Nausea	2/3 (66.7%)	2	1/1 (100%)	1
Sore throat	2/3 (66.7%)	2	0/1 (0%)	0
Flatulence	2/3 (66.7%)	2	0/1 (0%)	0
Visual changes (aura)	1/3 (33.3%)	1	0/1 (0%)	0
Pain (groin)	1/3 (33.3%)	1	0/1 (0%)	0
Cyst (outer labia)	1/3 (33.3%)	1	0/1 (0%)	0
Fall	1/3 (33.3%)	1	0/1 (0%)	0
Pain (left unla, radial head fracture)	1/3 (33.3%)	1	0/1 (0%)	0
Ear congestion	1/3 (33.3%)	1	0/1 (0%)	0
Heartburn	1/3 (33.3%)	1	0/1 (0%)	0
Pain	1/3 (33.3%)	1	0/1 (0%)	0
Diplopia	1/3 (33.3%)	1	0/1 (0%)	0
Pain (joint)	1/3 (33.3%)	1	0/1 (0%)	0
Heat intolerance	1/3 (33.3%)	1	0/1 (0%)	0
Cold intolerance	1/3 (33.3%)	1	0/1 (0%)	0
Joint function (stiffness)	1/3 (33.3%)	1	0/1 (0%)	0
Orthopnea	1/3 (33.3%)	1	0/1 (0%)	0
Muscle weakness (leg)	0/3 (0%)	0	1/1 (100%)	1
Dizziness	0/3 (0%)	0	1/1 (100%)	1
Constipation	0/3 (0%)	0	1/1 (100%)	1
Nervous system disorders
Neuropathy (numbness, tingling)	1/3 (33.3%)	1	0/1 (0%)	0
Renal and urinary disorders
Urinary frequency	1/3 (33.3%)	1	0/1 (0%)	0
Skin and subcutaneous tissue disorders
Hives (infusion reaction)	1/3 (33.3%)	1	0/1 (0%)	0
Hyperpigmentation (tongue)	2/3 (66.7%)	2	0/1 (0%)	0
Edema	1/3 (33.3%)	1	0/1 (0%)	0
Pruritic rash (left shoulder,chest)	1/3 (33.3%)	1	0/1 (0%)	0
Hyperpigmentation (hands, fingers)	1/3 (33.3%)	1	0/1 (0%)	0
Pruritic rash	1/3 (33.3%)	1	0/1 (0%)	0

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.