Ofatumumab With High Dose Methylprednisone Followed by Ofatumumab and Alemtuzumab in 17p CLL

CLL Clinical Trial

Official title:

A Phase II Study of Ofatumumab-High Dose Methylprednisolone Followed by Ofatumumab-Alemtuzumab in 17p Deletion CLL

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01465334
• Other study ID #: 11-304
• Secondary ID: NCCN Protocol Nu
• Status: Terminated
• Phase: Phase 2
• Start date: December 2011
• Est. completion date: January 2017

Study information

• Verified date: August 2023
• Source: Dana-Farber Cancer Institute
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The main purpose of this study is to examine how two separate groups of 17p deletion Chronic lymphocytic leukemia (CLL) participants respond to sequential treatment with this particular combination of drugs. The two groups are those participants who have previously received treatment for their CLL and those who have not yet received any treatment. The combination of drugs is Ofatumumab and High-Dose Methylprednisolone (HDMP) first followed by Ofatumumab and Alemtuzumab. All three drugs are FDA approved and have known activity in treating 17p CLL. We hope that by combining these drugs together in this study, they will have more benefit than each one alone and that the subjects' CLL will be significantly impacted.

Description:

Participants were assigned to 1 of 2 groups based on prior treatment status. Both groups received the same therapy.

Part A: Ofatumumab + HDMP 2-4 cycles Part B: Ofatumumab + Alemtuzumab 1-6 cycles Part C:

Maintenance with Ofatumumab + Alemtuzumab up to 2 years

Between days 15-22 of Cycle 2 of Part A, participants are restaged. Participants who achieve nodal complete response discontinue Part A therapy and undergo minimal residual disease (MRD) assessment to guide the decision whether to go to Part B or Part C. The participants with persistent disease after 2 cycles of Part A therapy receive 2 more cycles of Part A therapy and then undergo another restaging as well as MRD assessment. At restaging, participants with minimal disease are eligible for Part C or allogeneic stem cell transplant (SCT) off protocol. The remaining participants receive Part B therapy. On Part B, restaging occurs at weeks 12 and 18. If MRD negative complete response (CR) status is achieved then therapy is discontinued and the primary endpoint evaluation occurs 2 months later. Otherwise with persistent disease Part B therapy continues up to 24 weeks and the primary endpoint evaluation occurs after Part B therapy is completed. Participants who achieve clinical complete response may receive Part C therapy or be observed while waiting SCT.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 30
• Est. completion date: January 2017
• Est. primary completion date: November 2014
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Documented CLL/SLL

• 17p deletion by FISH in 20% or more nuclei on peripheral blood, bone marrow or lymph node

• Normal organ function

Exclusion Criteria:

• Pregnant or breast feeding

• Current active hepatic or biliary disease

• Chronic or current infectious disease requiring systemic antibiotics, antifungal, or antiviral treatment such as, but not limited to, chronic renal infection, tuberculosis and active Hepatitis C

• History of significant cerebrovascular disease in the past 6 months or ongoing event with active symptoms or sequelae

• Other past or current malignancy. Participants who have been free of malignancy for at least 2 years, or who have a history of completely resected non-melanoma skin cancer or successfully treated in situ carcinoma are eligible.

• Known HIV positive

• Clinically significant cardiac disease including unstable angina, acute myocardial infarction within 6 months prior to study entry, congestive heart failure, and arrhythmia unless controlled by therapy, with the exception of extra systoles or minor conduction abnormalities.

• Significant concurrent uncontrolled medical conditions including, but not limited to, renal, hepatic, gastrointestinal, endocrine, pulmonary, neurological, cerebral or psychiatric disease which in the opinion of the investigator may represent a risk for the subject.

• Positive serology for Hepatitis B or C

• History of allergic reactions attributed to ofatumumab.

Related Conditions & MeSH terms

• CLL
• SLL

Intervention

Drug:
• Ofatumumab

• High-Dose Methylprednisolone

• Alemtuzumab

Locations

Country	Name	City	State
United States	Beth Israel Deaconess Medical Center	Boston	Massachusetts
United States	Dana-Farber Cancer Institute	Boston	Massachusetts

Sponsors (3)

Lead Sponsor	Collaborator
Dana-Farber Cancer Institute	GlaxoSmithKline, National Comprehensive Cancer Network

Country where clinical trial is conducted

United States, 

References & Publications (1)

Davids MS, Kim HT, Yu L, De Maeyer G, McDonough M, Vartanov AR, Langey R, Fernandes SM, Hellman JM, Francoeur K, Arnason J, Jacobsen ED, LaCasce AS, Fisher DC, Brown JR. Ofatumumab plus high dose methylprednisolone followed by ofatumumab plus alemtuzumab — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Induction Overall Response Rate (ORR)	Induction ORR is the percentage of participants achieving a minimum of partial response (PR) over induction treatment based on International Workshop on Chronic Lymphocytic Leukemia (IW-CLL) criteria (Hallek, et al 2008). There are numerous diagnostic tests used for response evaluation including potentially CBC and differential count, marrow aspirate and biopsy, ultrasound of the abdomen, CT scans (chest, pelvis, abdomen) and physical examination. PR is a 50% or greater decrease of measured size of lymphadenopathy, hepatomegaly, splenomegaly as well as blood lymphocytes (over baseline), marrow infiltrate or B-lymphoid nodules and a 50% or greater increase from baseline in platelet count (or level >100,000/micro liter), hemoglobin (or level >11 grams/deciliter), neutrophils (or level >1500/microliter).	Disease was evaluated after weeks 8 and 16 of Part A and at 12, 18 and 24 weeks during part B.
Secondary	Number of Participants Achieving Induction Complete Response (CR)	CR over induction treatment was based on International Workshop on Chronic Lymphocytic Leukemia (IW-CLL) criteria (Hallek, et al 2008). There are numerous diagnostic tests used for response evaluation including potentially CBC and differential count, marrow aspirate and biopsy, ultrasound of the abdomen, CT scans (chest, pelvis, abdomen) and physical examination. CR is absence of significant lymphadenopathy (nodes<1.5 centimeters in long axis diameter), hepatomegaly, splenomegaly as well as blood lymphocytes<4000/microliter, normocellular for age marrow with <30% lymphocytes, no B-lymphoid nodules and platelet>100,000/micro liter, hemoglobin>11 grams/deciliter, neutrophils>1500/microliter.	Disease was evaluated after weeks 8 and 16 of Part A and at 12, 18 and 24 weeks during part B.
Secondary	Overall Objective Response Rate (ORR)	Overall ORR is the percentage of participants achieving a minimum of partial response (PR) over induction and maintenance treatment based on International Workshop on Chronic Lymphocytic Leukemia (IW-CLL) criteria (Hallek, et al 2008). There are numerous diagnostic tests used for response evaluation including potentially CBC and differential count, marrow aspirate and biopsy, ultrasound of the abdomen, CT scans (chest, pelvis, abdomen) and physical examination. PR is a 50% or greater decrease of measured size of lymphadenopathy, hepatomegaly, splenomegaly as well as blood lymphocytes (over baseline), marrow infiltrate or B-lymphoid nodules and a 50% or greater increase from baseline in platelet count (or level >100,000/micro liter), hemoglobin (or level >11 grams/deciliter), neutrophils (or level >1500/microliter).	Disease was evaluated after weeks 8 and 16 of Part A, at 12, 18 and 24 weeks during part B and every 6 months on Part C.
Secondary	Number of Participants With Overall CR	CR overall (induction and maintenance treatment) was based on International Workshop on Chronic Lymphocytic Leukemia (IW-CLL) criteria (Hallek, et al 2008). There are numerous diagnostic tests used for response evaluation including potentially CBC and differential count, marrow aspirate and biopsy, ultrasound of the abdomen, CT scans (chest, pelvis, abdomen) and physical examination. CR is absence of significant lymphadenopathy (nodes<1.5 centimeters in long axis diameter), hepatomegaly, splenomegaly as well as blood lymphocytes<4000/microliter, normocellular for age marrow with <30% lymphocytes, no B-lymphoid nodules and platelet>100,000/micro liter, hemoglobin>11 grams/deciliter, neutrophils>1500/microliter.	Disease was evaluated after weeks 8 and 16 of Part A, at 12, 18 and 24 weeks during part B and every 6 months on Part C.
Secondary	Overall MRD Negative Rate	Overall MRD negative rate is the percentage of participants classified as MRD negative by four color flow cytometry. The assay has a sensitivity of 1 in 10,000 leukocytes.	MRD was assessed after weeks 8 and 16 of Part A, at 12, 18 and 24 weeks during part B and every 6 months on Part C.
Secondary	Transplant Rate	Percentage of participants eligible for allogeneic hematopoietic stem cell transplantation (alloHSCT) that are able and willing to proceed to alloHSCT.	Evaluated up to 36 cycles (approximately 2.75 years) of treatment (Parts A, B and C)
Secondary	Number of Participants With Treatment-Related Grades 1-3 Hyperglycemia During Part A Induction	Participants ever experiencing a grade 1-3 hyperglycemia event based on CTCAEv4 with treatment attribution of possible, probably or definite as reported on case report forms were counted.	Adverse Events (AEs) were collected weekly during cycle 1 Part A and then every other week for the duration of Part A (up to 16 weeks)
Secondary	3-Year Progression-Free Survival (PFS) Probability	3-year PFS is the probability of participants remaining alive and progression-free at 3 years from study entry estimated using Kaplan-Meier methods. Disease progression (PD) per International Workshop on Chronic Lymphocytic Leukemia (IW-CLL) criteria (Hallek, et al 2008) is: the appearance of any new lesion (enlarged lymph node minimum >1.5 centimeters); an increase by 50% in greatest determined diameter of any previous site; an increase in the previously noted enlargement of the liver or spleen by 50% or more or the de novo appearance of hepatomegaly, splenomegaly; a 50% increase of blood lymphocytes (over baseline with level at least 5,000/microliter); occurrence of cytopenia secondary to CLL at least 3 months post treatment including a 50% or greater decrease from baseline in platelet count (or level <100,000/microliter) or a hemoglobin decrease of >2 grams/deciliter (or level <10 grams/deciliter); and transformation to a more aggressive histology.	Disease was evaluated on treatment after weeks 8 and 16 of Part A, at 12, 18 and 24 weeks during part B and every 6 months on Part C as well as off-treatment every 3 months up to 5 years.
Secondary	3-year Overall Survival (OS) Probability	3-year OS is the probability of participants remaining alive at 3 years from study entry estimated using Kaplan-Meier methods.	Median survival follow-up was 45 months (range 31-58 months) in this study cohort.
Secondary	Number of Participants Completing Part A Treatment	Participants counted as completing Part A with either 2 or 4 cycles of treatment per protocol.	Evaluated up to 4 cycles/16 weeks.
Secondary	Number of Participants Completing Only 2 Cycles of Part A Treatment	Participants counted if only completed 2 cycles of Part A treatment per protocol.	Evaluated after 2 cycles/8 weeks of Part A therapy.