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A Study of De-immunized DI-Leu16-IL2 Administered Subcutaneously in Participants With B-cell NHL (DI-Leu16-IL2)

Primary Purpose

B-cell Non-Hodgkin Lymphoma

Status

Terminated

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

DI-Leu16-IL2

About this trial

This is an interventional treatment trial for B-cell Non-Hodgkin Lymphoma focused on measuring NHL, Immunocytokine, Lymphoma, Non-Hodgkin, B-cell, IL (interleukin)

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Participants with CD20-expressing B-cell NHL that is relapsed or refractory to standard therapy. Chronic lymphocytic leukemia/small lymphocytic lymphoma with peripheral blood leukemia/lymphoma cells and high-grade lymphomas are excluded.
Participants must have received prior rituximab-containing therapy.
Evaluable disease. In the absence of lymphadenopathy, splenomegaly with defects or measurable extra-medullary disease is acceptable.
Participants who have received a prior autologous stem cell transplant are eligible if the transplant occurred >6 months ago.
Participants who have received a prior allogeneic stem cell transplant are eligible if:
1. The transplant occurred >6 months ago
2. There is no evidence of active graft versus host disease
3. Systemic immunosuppressive agents (including corticosteroids) have not been received for at least 8 weeks
Karnofsky performance scale ≥70%
Life expectancy ≥12 weeks
Adequate baseline functions:
1. Serum creatinine ≤1.5 mg/deciliter (dL)
2. Total white blood cell (WBC) count ≥3000/microliter (µL) or absolute neutrophil count (ANC) ≥1000/µL
3. Absolute lymphocyte count ≥0.75 * 10^3/µL
4. Platelet count ≥75,000/µL
5. Hematocrit ≥25% or hemoglobin ≥9 grams/100 milliliters (mL)
6. Alanine aminotransferase (ALT) <2.5 * upper limit of normal (ULN)
7. Aspartate aminotransferase (AST) <2.5 * ULN
8. Total bilirubin (TBili) <1.5 * ULN
9. Sodium, potassium, and phosphorus levels no worse than grade 1
10. Chest x-ray (CXR) or computed tomography (CT) within 4 weeks prior to Day 1 with no evidence of pulmonary congestion, pleural effusions, pulmonary fibrosis, or significant emphysema. If results are questionable, participants should have additional lung function testing to exclude clinically relevant restriction or obstruction. Participants must have a forced expiratory volume (FEV-1) and diffusing capacity of the lung for carbon monoxide (DLCO) of at least 65% and 50% of expected, respectively.
11. Electrocardiogram (12-lead ECG) QTc ≤480 millisecond (ms)
12. Cardiac stress test (for example, stress thallium scan, stress echocardiography) with normal results if participant is suspected to have coronary artery disease.
Participants participating in the study are to use adequate birth control measures (abstinence, oral contraceptives, barrier method with spermicide or surgical sterilization) during the study. Females of childbearing potential must have a negative serum pregnancy test on the days of dosing. A female of childbearing potential is a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (that is, has had menses at any time in the preceding 24 consecutive months).
Provide written informed consent prior to any screening procedures

Exclusion Criteria:

Evidence of central nervous system lymphoma or lymphomatous meningitis
Prior treatment with interleukin 2 (IL2) within the last 5 years
Type I hypersensitivity or anaphylactic reactions to murine proteins or to previous infusion of rituximab
Pregnant or lactating female
An immediate need for palliative radiotherapy or systemic corticosteroid therapy
Known intercurrent infections (including hepatitis C virus and human immunodeficiency virus or other conditions), or clinical evidence of these conditions
Actively infected with or chronic carriers of hepatitis B virus as demonstrated by positive hepatitis B core antibody or hepatitis B surface antigen. Participants who are seropositive only, that is, surface antibody positive [HbsAb], are permitted.
Other significant active infection.
Major surgery, chemotherapy, investigational agent, or radiation within 30 days of Day 1
Uncontrolled hypertension (diastolic greater to or equal to 100 millimeters of mercury [mmHg]) or hypotension (systolic less than or equal to 90 mmHg)
History of repeated and clinically relevant episodes of syncope or other paroxysmal, ventricular, or other significant arrhythmias
History of medically significant ascites requiring repetitive paracentesis
Previous diagnosis of autoimmune disease (Exceptions: participants with autoimmune thyroiditis or vitiligo may be enrolled)
Organ transplant recipient
History of prior therapy or a serious, uncontrolled medical disorder that in the Investigator's opinion would impair participation in the study
Known hypersensitivity to Tween-80 or human immunoglobulin
Legal incapacity or limited legal capacity
Participants with bulky lymph nodes (LNs) (≥10 centimeters [cm]) or marked splenomegaly (that is, extending into pelvis or crossing the midline).
Circulating levels of rituximab >75.0 micrograms (µg)/mL

Sites / Locations

City of Hope
St. Jude Hospital Yorba Linda
University of Minnesota
Dartmouth-Hitchcock Medical Center
Joe Arlington Cancer Research and Treatment Center

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm Type

Experimental

Arm Label

DI-Leu16-IL2 0.5 mg/m^2

DI-Leu16-IL2 1.0 mg/m^2

DI-Leu16-IL2 2.0 mg/m^2

DI-Leu16-IL2 4.0 mg/m^2

DI-Leu16-IL2 6.0 mg/m^2

Arm Description

Participants will receive DI-Leu16-IL2 0.5 mg/m^2 subcutaneously (SC) for 3 consecutive days every 3 weeks (21-day cycle) for a total of 4 cycles.

Participants will receive DI-Leu16-IL2 1.0 mg/m^2 SC for 3 consecutive days every 3 weeks (21-day cycle) for a total of 4 cycles.

Participants will receive DI-Leu16-IL2 2.0 mg/m^2 SC for 3 consecutive days every 3 weeks (21-day cycle) for a total of 4 cycles.

Participants will receive DI-Leu16-IL2 4.0 mg/m^2 SC for 3 consecutive days every 3 weeks (21-day cycle) for a total of 4 cycles

Participants will receive DI-Leu16-IL2 6.0 mg/m^2 SC for 3 consecutive days every 3 weeks (21-day cycle) for a total of 4 cycles.

Outcomes

Primary Outcome Measures

Maximum Tolerated Dose (MTD) of DI-Leu16-IL2

The MTD was determined based on toxicities from the first 2 cycles of treatment. The MTD was the highest dose tested with no more than 1 participant out of 6 experienced a dose-limiting toxicity (DLT). All non-hematologic adverse events (AEs) and all hematologic AEs of greater than Grade 3 were considered relevant to determining DLTs. DLTs included absolute lymphocyte count (ALC) Grade 3 and 4 (if ALC does not resolve to baseline grade according to Common Terminology Criteria for Adverse Events (CTCAE) v4 within 5 days post the final injection per cycle of DI-Leu16-IL2), and absolute neutrophil count (ANC) Grade 3 (If ANC does not resolve to at least Grade 2 within 5 days post the final injection per cycle of DI-Leu16-IL2) and Grade 4 (any).

Number of Participants With a DLT

All non-hematologic AEs and all hematologic AEs of greater than Grade 3 were considered relevant to determining DLTs. DLTs included ALC Grade 3 and 4 (if ALC does not resolve to baseline grade according to CTCAE v4 within 5 days post the final injection per cycle of DI-Leu16-IL2), and ANC Grade 3 (If ANC does not resolve to at least Grade 2 within 5 days post the final injection per cycle of DI-Leu16-IL2) and Grade 4 (any).

Number of Participants With Best Overall Response (BOR) Assessed Per International Workshop for Non-Hodgkin Lymphoma (NHL) Response Criteria

BOR included complete response (CR), unconfirmed CR (CRu), partial response (PR), stable disease (SD), and progressive disease (PD). CR: 1) Disappearance of all detectable clinical and radiological evidence of disease; 2) lymph nodes (LN) regressed to normal size; 3) other organs (spleen, liver, kidneys) that were enlarged before therapy must have decreased in size; 4) clear bone marrow (BM) infiltrate. CRu: must meet CR criteria 1 and 3, as well as ≥1 of following: residual LN mass >1.5 cm in greatest transverse diameter; individual nodes that were previously confluent regressed by >75% in sum of product diameters (SPD); or indeterminate BM. PR: 6 largest dominant nodes or nodal masses decreased by ≤50% in SPD; no increase in size of other nodes; liver or spleen; splenic and hepatic nodules regressed ≥50% in SPD; and no new disease. SD: less than a PR but not PD. PD: 50% increase from nadir in SPD of any abnormal node for PR or nonresponders and appearance of any new lesion.

Tumor Measurement: Percent Change From Baseline in Sum of Product of Diameters at the End of Study

Sum of product diameters sums the product of the 2 tumor measurements on each lesion. If only 1 measurement was available, it was used as the longest length and the product of the lengths in the sum. Baseline value is the last non-missing measurement prior to receiving study drug injection. None of the participants were considered evaluable in 'DI-Leu16-IL2 0.5 mg/m^2' arm for this outcome measure at the end of study, and therefore, data were not collected for that arm.

Tumor Measurement: Percent Change From Baseline in Sum of Longest Diameters at the End of Study

Sum of longest diameters is the sum of the longest measured length of each tumor lesion. Baseline value is the last non-missing measurement prior to receiving study drug injection. None of the participants were considered evaluable in 'DI-Leu16-IL2 0.5 mg/m^2' arm for this outcome measure at the end of study, and therefore, data were not collected for that arm.

Secondary Outcome Measures

Number of Participants With Anti-DI-Leu16-IL2 Antibodies

Full Information

NCT ID

NCT01874288

First Posted

June 7, 2013

Last Updated

November 2, 2020

Sponsor

Alopexx Oncology, LLC

1. Study Identification

Unique Protocol Identification Number

NCT01874288

Brief Title

A Study of De-immunized DI-Leu16-IL2 Administered Subcutaneously in Participants With B-cell NHL

Acronym

DI-Leu16-IL2

Official Title

A Phase I/II Study of De-immunized DI-Leu16-IL2 Immunocytokine Administered Subcutaneously in Patients With B-cell Non-Hodgkin Lymphoma (NHL)

Study Type

Interventional

2. Study Status

Record Verification Date

November 2020

Overall Recruitment Status

Terminated

Why Stopped

Clinical benefit was noted in the earlier portion of the trial; hence, participants were not enrolled in 2 expansion cohorts and the study was terminated early.

Study Start Date

November 25, 2013 (Actual)

Primary Completion Date

January 27, 2014 (Actual)

Study Completion Date

November 16, 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Alopexx Oncology, LLC

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

This dose-escalation study is designed for determining the safety, tolerability, pharmacokinetics (PK), biological, and clinical activity of DI-Leu16-IL2 administered to participants with cluster of differentiation 20 (CD20) positive NHL that have failed standard rituximab-containing therapy.

Detailed Description

The participants will be enrolled during dose escalation and during 2 expansion cohorts of up to 12 participants each. The dose escalation portion of the trial will incorporate a modified accelerated titration design. Therefore, the trial will enroll 3 participants per dose level with a doubling of the dose at each level during the accelerated stage of the study (skipping every other dose level). Once the first instance of any Grade 3 or higher treatment related toxicity (with some notable exceptions) is observed on the first cycle, the accelerated stage will end and the trial will revert to a conventional design using cohorts of 3 or 6 participants (standard 3+3 design), with single step 2 milligrams (mg)/square meter (m^2) increments. To further explore the clinical efficacy, additional participants (up to 12 per cohort) may be enrolled at the optimal biologic dose (OBD) or maximum tolerated dose (MTD). At the end of the study, participants may be enrolled into an open-label extension study (AO-101-EXT [NCT02151903]), at the discretion of the investigator.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

B-cell Non-Hodgkin Lymphoma

Keywords

NHL, Immunocytokine, Lymphoma, Non-Hodgkin, B-cell, IL (interleukin)

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Sequential Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

24 (Actual)

8. Arms, Groups, and Interventions

Arm Title

DI-Leu16-IL2 0.5 mg/m^2

Arm Type

Experimental

Arm Description

Participants will receive DI-Leu16-IL2 0.5 mg/m^2 subcutaneously (SC) for 3 consecutive days every 3 weeks (21-day cycle) for a total of 4 cycles.

Arm Title

DI-Leu16-IL2 1.0 mg/m^2

Arm Type

Experimental

Arm Description

Participants will receive DI-Leu16-IL2 1.0 mg/m^2 SC for 3 consecutive days every 3 weeks (21-day cycle) for a total of 4 cycles.

Arm Title

DI-Leu16-IL2 2.0 mg/m^2

Arm Type

Experimental

Arm Description

Participants will receive DI-Leu16-IL2 2.0 mg/m^2 SC for 3 consecutive days every 3 weeks (21-day cycle) for a total of 4 cycles.

Arm Title

DI-Leu16-IL2 4.0 mg/m^2

Arm Type

Experimental

Arm Description

Participants will receive DI-Leu16-IL2 4.0 mg/m^2 SC for 3 consecutive days every 3 weeks (21-day cycle) for a total of 4 cycles

Arm Title

DI-Leu16-IL2 6.0 mg/m^2

Arm Type

Experimental

Arm Description

Participants will receive DI-Leu16-IL2 6.0 mg/m^2 SC for 3 consecutive days every 3 weeks (21-day cycle) for a total of 4 cycles.

Intervention Type

Drug

Intervention Name(s)

DI-Leu16-IL2

Intervention Description

DI-Leu16-IL2 will be administered per dose and schedule specified in the arm.

Primary Outcome Measure Information:

Title

Maximum Tolerated Dose (MTD) of DI-Leu16-IL2

Description

Time Frame

First 2 cycles of treatment (each cycle = 21 days)

Title

Number of Participants With a DLT

Description

Time Frame

First 2 cycles of treatment (each cycle = 21 days)

Title

Number of Participants With Best Overall Response (BOR) Assessed Per International Workshop for Non-Hodgkin Lymphoma (NHL) Response Criteria

Description

Time Frame

First dose of study drug until first appearance of CR, CRu, PR, SD, or PD (up to 6 months)

Title

Tumor Measurement: Percent Change From Baseline in Sum of Product of Diameters at the End of Study

Description

Time Frame

Baseline, end of study (EOS) (up to approximately 3 years)

Title

Tumor Measurement: Percent Change From Baseline in Sum of Longest Diameters at the End of Study

Description

Time Frame

Baseline, EOS (up to approximately 3 years)

Secondary Outcome Measure Information:

Title

Number of Participants With Anti-DI-Leu16-IL2 Antibodies

Time Frame

First dose of study drug up to EOS (up to approximately 3 years)

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Participants with CD20-expressing B-cell NHL that is relapsed or refractory to standard therapy. Chronic lymphocytic leukemia/small lymphocytic lymphoma with peripheral blood leukemia/lymphoma cells and high-grade lymphomas are excluded. Participants must have received prior rituximab-containing therapy. Evaluable disease. In the absence of lymphadenopathy, splenomegaly with defects or measurable extra-medullary disease is acceptable. Participants who have received a prior autologous stem cell transplant are eligible if the transplant occurred >6 months ago. Participants who have received a prior allogeneic stem cell transplant are eligible if: The transplant occurred >6 months ago There is no evidence of active graft versus host disease Systemic immunosuppressive agents (including corticosteroids) have not been received for at least 8 weeks Karnofsky performance scale ≥70% Life expectancy ≥12 weeks Adequate baseline functions: Serum creatinine ≤1.5 mg/deciliter (dL) Total white blood cell (WBC) count ≥3000/microliter (µL) or absolute neutrophil count (ANC) ≥1000/µL Absolute lymphocyte count ≥0.75 * 10^3/µL Platelet count ≥75,000/µL Hematocrit ≥25% or hemoglobin ≥9 grams/100 milliliters (mL) Alanine aminotransferase (ALT) <2.5 * upper limit of normal (ULN) Aspartate aminotransferase (AST) <2.5 * ULN Total bilirubin (TBili) <1.5 * ULN Sodium, potassium, and phosphorus levels no worse than grade 1 Chest x-ray (CXR) or computed tomography (CT) within 4 weeks prior to Day 1 with no evidence of pulmonary congestion, pleural effusions, pulmonary fibrosis, or significant emphysema. If results are questionable, participants should have additional lung function testing to exclude clinically relevant restriction or obstruction. Participants must have a forced expiratory volume (FEV-1) and diffusing capacity of the lung for carbon monoxide (DLCO) of at least 65% and 50% of expected, respectively. Electrocardiogram (12-lead ECG) QTc ≤480 millisecond (ms) Cardiac stress test (for example, stress thallium scan, stress echocardiography) with normal results if participant is suspected to have coronary artery disease. Participants participating in the study are to use adequate birth control measures (abstinence, oral contraceptives, barrier method with spermicide or surgical sterilization) during the study. Females of childbearing potential must have a negative serum pregnancy test on the days of dosing. A female of childbearing potential is a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (that is, has had menses at any time in the preceding 24 consecutive months). Provide written informed consent prior to any screening procedures Exclusion Criteria: Evidence of central nervous system lymphoma or lymphomatous meningitis Prior treatment with interleukin 2 (IL2) within the last 5 years Type I hypersensitivity or anaphylactic reactions to murine proteins or to previous infusion of rituximab Pregnant or lactating female An immediate need for palliative radiotherapy or systemic corticosteroid therapy Known intercurrent infections (including hepatitis C virus and human immunodeficiency virus or other conditions), or clinical evidence of these conditions Actively infected with or chronic carriers of hepatitis B virus as demonstrated by positive hepatitis B core antibody or hepatitis B surface antigen. Participants who are seropositive only, that is, surface antibody positive [HbsAb], are permitted. Other significant active infection. Major surgery, chemotherapy, investigational agent, or radiation within 30 days of Day 1 Uncontrolled hypertension (diastolic greater to or equal to 100 millimeters of mercury [mmHg]) or hypotension (systolic less than or equal to 90 mmHg) History of repeated and clinically relevant episodes of syncope or other paroxysmal, ventricular, or other significant arrhythmias History of medically significant ascites requiring repetitive paracentesis Previous diagnosis of autoimmune disease (Exceptions: participants with autoimmune thyroiditis or vitiligo may be enrolled) Organ transplant recipient History of prior therapy or a serious, uncontrolled medical disorder that in the Investigator's opinion would impair participation in the study Known hypersensitivity to Tween-80 or human immunoglobulin Legal incapacity or limited legal capacity Participants with bulky lymph nodes (LNs) (≥10 centimeters [cm]) or marked splenomegaly (that is, extending into pelvis or crossing the midline). Circulating levels of rituximab >75.0 micrograms (µg)/mL

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Daniel Vlock, MD

Organizational Affiliation

Alopexx Oncology, LLC

Official's Role

Study Director

Facility Information:

Facility Name

City of Hope

City

Duarte

State/Province

California

ZIP/Postal Code

91010

Country

United States

Facility Name

St. Jude Hospital Yorba Linda

City

Fullerton

State/Province

California

ZIP/Postal Code

92835

Country

United States

Facility Name

University of Minnesota

City

Minneapolis

State/Province

Minnesota

ZIP/Postal Code

55455

Country

United States

Facility Name

Dartmouth-Hitchcock Medical Center

City

Lebanon

State/Province

New Hampshire

ZIP/Postal Code

03756

Country

United States

Facility Name

Joe Arlington Cancer Research and Treatment Center

City

Lubbock

State/Province

Texas

ZIP/Postal Code

97410

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

Citations:

PubMed Identifier

15483010

Citation

King DM, Albertini MR, Schalch H, Hank JA, Gan J, Surfus J, Mahvi D, Schiller JH, Warner T, Kim K, Eickhoff J, Kendra K, Reisfeld R, Gillies SD, Sondel P. Phase I clinical trial of the immunocytokine EMD 273063 in melanoma patients. J Clin Oncol. 2004 Nov 15;22(22):4463-73. doi: 10.1200/JCO.2004.11.035. Epub 2004 Oct 13.

Results Reference

background

PubMed Identifier

15076141

Citation

Ko YJ, Bubley GJ, Weber R, Redfern C, Gold DP, Finke L, Kovar A, Dahl T, Gillies SD. Safety, pharmacokinetics, and biological pharmacodynamics of the immunocytokine EMD 273066 (huKS-IL2): results of a phase I trial in patients with prostate cancer. J Immunother. 2004 May-Jun;27(3):232-9. doi: 10.1097/00002371-200405000-00008.

Results Reference

background

PubMed Identifier

7522629

Citation

Maloney DG, Liles TM, Czerwinski DK, Waldichuk C, Rosenberg J, Grillo-Lopez A, Levy R. Phase I clinical trial using escalating single-dose infusion of chimeric anti-CD20 monoclonal antibody (IDEC-C2B8) in patients with recurrent B-cell lymphoma. Blood. 1994 Oct 15;84(8):2457-66.

Results Reference

background

Links:

URL

http://www.alopexx.com

Description

Sponsor website

URL

http://www.cancer.gov/cancertopics/types/non-hodgkin

Description

National Cancer Institute at the National Institute of Health

Learn more about this trial

A Study of De-immunized DI-Leu16-IL2 Administered Subcutaneously in Participants With B-cell NHL

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