A Phase 1/2 interventional study of milatuzumab and veltuzumab in Lymphoma, sponsored by Beth Christian. Completed at 1 site in United States. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2017-02-06.
Sponsored by Beth Christian · Phase 1/2, Interventional, and Treatment
A phase I dose escalation study of veltuzumab and milatuzumab in relapsed and refractory B-cell NHL. The phase I study will be followed by a pilot phase II study.
A phase I/II study of veltuzumab combined with milatuzumab in relapsed and refractory non-Hodgkin's lymphoma. Both agents are well-tolerated in early phase clinical testing with infusion reactions as the primary observed toxicity. Preclinical testing in vitro and in vivo have demonstrated single agent activity for both veltuzumab and milatuzumab. In mantle cell lymphoma cell lines and SCID mouse models, synergist effects were observed when milatuzumab was combined with rituximab. Veltuzumab has several advantages over rituximab including slower off-rates, shorter infusion times, higher potency, and improved therapeutic responses in animal models. Previous and ongoing clinical investigations support the concept of combining monoclonal antibodies in NHL.
5,578 studies on the registry are indexed under Lymphoma; 825 are open to participants now.
This study's enrollment of 35 is below the median of 40 across 4,508 interventional studies indexed under Lymphoma.
Browse Lymphoma studies →Beth Christian is the lead sponsor of 3 studies on the registry; none are open to participants now.
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Histologically confirmed B-cell non-Hodgkin lymphoma (NHL), including any of the following:
Patients must have normal organ and marrow function as defined below:
Phase II
-Must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension >10 mm or in the case of Waldenstrom's macroglobulinemia, the presence of an IgM paraprotein level 2x the upper limit of normal.
Exclusion Criteria:
Phase I portion of the study, a standard 3+3 dose escalation schema will be followed. Patients will receive veltuzumab IV weekly on day 1 for 4 doses and milatuzumab weekly on for 4 total doses during induction therapy. Induction therapy will be defined as the first 4 weeks of study therapy. During week 1 of induction therapy, patients will receive veltuzumab alone on day 1 and milatuzumab alone on day 2 to prevent overlapping infusion reactions. Starting week 2, veltuzumab will be given on day 1 and milatuzumab will be given on day 4.
Biological: milatuzumab · Biological: veltuzumab · Procedure: Correlative/Special Studies · Procedure: Quantitative T-, B-, and NK cell subsets · Procedure: Pharmacokinetics · Procedure: Human Anti-Human Antibodies
Patients will receive veltuzumab IV weekly for 4 doses and milatuzumab IV weekly on day 2 of week 1 and on day 4 of weeks 2-4 for 4 total doses during induction therapy. Patients may continue on therapy to receive extended induction therapy provided they do not experience significant toxicity or rapid disease progression during the initial 4 week induction.
Biological: veltuzumab and milatuzumab
Patient will receive milatuzumab weekly for 4 total doses during induction therapy. Induction therapy will be defined as the first 4 weeks of study therapy. During week 1 of induction therapy, patients will receive milatuzumab on day 2. Starting in week 2, milatuzumab will be given on day 4. Provided the patient does not experience excessive toxicity or disease progression during induction therapy, the patient may continue treatment with extended induction therapy, consisting of veltuzumab day 1 and milatuzumab day 4 of weeks 12, 20, 28, and 36.
Also known as: monoclonal antibody
Patient will receive veltuzumab weekly for 4 total doses during induction therapy. Induction therapy will be defined as the first 4 weeks of study therapy. Provided the patient does not experience excessive toxicity or disease progression during induction therapy, the patient may continue treatment with extended induction therapy, consisting of veltuzumab day 1 and milatuzumab day 4 of weeks 12, 20, 28, and 36.
Also known as: monoclonal antibody
To correlate Fcγ receptor polymorphisms with response to treatment with the combination of veltuzumab and milatuzumab. Whole blood will be collected pre-treatment on day 1.
Also known as: blood samples
Quantitative T-, B-, and NK- cell subsets will be assessed using flow cytometry to quantify the percentage and absolute number of cells expressing CD4, CD8, CD56, CD16, CD19, and CD20 pre-treatment on day 1, after induction (week 5, day 1), and prior to the start of therapy on day 1 week 12, day 1 week 36, and then every 4 months for one year.
Also known as: blood samples
To assess the pharmacokinetics of veltuzumab in patients with relapsed or refractory B-cell non-Hodgkin's lymphoma. Pharmacokinetics will be assessed with blood samples collected at the following time points: immediately pre- and post-infusion on day 1 of weeks 1, 2, 4, 12 and 36. One additional sample will be collected each of weeks 5 through 10 (sample may be collected any day during each of these weeks).
Also known as: blood samples
To assess the pharmacokinetics of milatuzumab in patients with relapsed or refractory B-cell non-Hodgkin's lymphoma. Pharmacokinetics will be assessed with blood samples collected at the following time points: immediately pre- and post-infusion on day 2 of week 1 and day 1 of weeks 2, 4, 12 and 36. Additional samples will be collected days 3 through 6 of week 1.
Also known as: blood samples
To monitor for the development of human anti-veltuzumab antibodies and human anti-milatuzumab antibodies (HAHA) in patients receiving treatment with veltuzumab and milatuzumab. Patients will be monitored for the development of HAHA at the following timepoints: pre-treatment on day 1 of week 1, pre-treatment on day 1 of week 4, pre-treatment on day 1 of week 12, and pre-treatment on day 1 of week 36.
Also known as: blood samples
Patient will receive veltuzumab and milatuzumab weekly for 4 total doses during induction therapy. Induction therapy will be defined as the first 4 weeks of study therapy. During week 1 of induction therapy, patients will receive veltuzumab on day 1 and milatuzumab on day 2. Starting in week 2, veltuxumab will be given on day 1 and milatuzumab will be given on day 4. Provided the patient does not experience excessive toxicity or disease progression during induction therapy, the patient may continue treatment with extended induction therapy, consisting of veltuzumab day 1 and milatuzumab day 4 of weeks 12, 20, 28, and 36.
Also known as: monoclonal antibody
Dose Limiting Toxicity (DLT) for Phase I Patients
Dose-limiting toxicity was assessed during induction therapy for phase I.
Time frame: up to 2 years
Maximum Tolerated Dose (MTD)for Phase I Patients
Patients received a fixed dose of Veltuzumab IV 200 mg/m2 and Milatuzumab was dose escalated
Time frame: up to 2 years
Overall Objective Response Rate
Per International Response Criteria (Cheson JCO 2007) for target lesions and assessed by CT, MRI or PET: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=50% decrease in sum of the product of the diameters (SPD) of up to six of the largest dominant nodes or nodal masses; Overall Response (OR) = CR + PR.
Time frame: Up to 2 years
Progression-free Survival (PFS)
Progression is defined using International Response Criteria (Cheson JCO 2007), as a \>= 50% increase from nadir in the SPD of any previously involved nodes, or in a single involved node, or at least a 50% increase in the longest diameter of any single previously identified node more than 1 cm in its short axis, or the size of other lesions (eg, splenic or hepatic nodules), or the appearance of new lesions.
Time frame: up to 2 years
Fcγ-receptor Polymorphism Response to Treatment
The relationship between overall response rate (ORR) and Fcy receptor status. A two-sided chi-square test or exact test with α = 0.05 will be used to test the homogeneity of the ORR among the three genotypes.
Time frame: up to 2 years
Quantitative T-, B-, and NK-cell Subsets Using Flow Cytometry
Quantitative T-, B-, and NK- cell subsets will be assessed using flow cytometry to quantify the percentage and absolute number of cells expressing CD4, CD8, CD56, CD16, CD19, and CD20 at screening, after induction, and prior to the start of therapy on day 1 week 12, day 1 week 28, and then every 4 months for one year.
Time frame: up to 1 year
Access Pharmacokinetics Through AUC0-∞ (Area Under Curve)
Evaluation of pharmacokinetics (Pk) of veltuzumab and milatuzumab was performed for patients included in the trial. Statistically, descriptive data of PK parameters will be computed. Relationships between such parameters as dose and AUC, volume of distribution, clearance, and others will be evaluated, but be preliminary due to the small sample size.
Time frame: 0, 24, 48, 72, 96 and 120 hours post-does
Access Pharmacokinetics Through Cmax
Evaluation of pharmacokinetics of veltuzumab and milatuzumab was performed for patients included in the trial. Statistically, descriptive data of PK parameters will be computed. Relationships between such parameters as dose and AUC, volume of distribution, clearance, and others will be evaluated, but be preliminary due to the small sample size.
Time frame: 0, 24, 48, 72, 96 and 120 hours post-dose
Monitor Human Anti-veltuzumab Antibodies and Human Anti-milatuzumab (HAHA)
Patients will be monitored for the development of human anti-veltuzumab antibodies and human anti-milatuzumab antibodies (HAHA).
Time frame: up to 36 weeks
| Milestone | Phase I | Phase II |
|---|---|---|
| Started | 18 | 17 |
| Completed | 18 | 17 |
| Not completed | 0 | 0 |
Dose-limiting toxicity was assessed during induction therapy for phase I.
| patients | Phase I |
|---|---|
| Dose Limiting Toxicity (DLT) for Phase I Patients | 0 |
Patients received a fixed dose of Veltuzumab IV 200 mg/m2 and Milatuzumab was dose escalated
| mg/kg | Phase I |
|---|---|
| Maximum Tolerated Dose (MTD)for Phase I Patients | 20 |
Per International Response Criteria (Cheson JCO 2007) for target lesions and assessed by CT, MRI or PET: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=50% decrease in sum of the product of the diameters (SPD) of up to six of the largest dominant nodes or nodal masses; Overall Response (OR) = CR + PR.
| percent of patients | All Patients From Phase I and Phase II |
|---|---|
| Overall Objective Response Rate | 24 |
Progression is defined using International Response Criteria (Cheson JCO 2007), as a \>= 50% increase from nadir in the SPD of any previously involved nodes, or in a single involved node, or at least a 50% increase in the longest diameter of any single previously identified node more than 1 cm in its short axis, or the size of other lesions (eg, splenic or hepatic nodules), or the appearance of new lesions.
| months | All Patients From Phase I and Phase II |
|---|---|
| Progression-free Survival (PFS) | 4.7 (2.2 to 9.3) |
The relationship between overall response rate (ORR) and Fcy receptor status. A two-sided chi-square test or exact test with α = 0.05 will be used to test the homogeneity of the ORR among the three genotypes.
No measurements were reported for this outcome.
Quantitative T-, B-, and NK- cell subsets will be assessed using flow cytometry to quantify the percentage and absolute number of cells expressing CD4, CD8, CD56, CD16, CD19, and CD20 at screening, after induction, and prior to the start of therapy on day 1 week 12, day 1 week 28, and then every 4 months for one year.
No measurements were reported for this outcome.
Evaluation of pharmacokinetics (Pk) of veltuzumab and milatuzumab was performed for patients included in the trial. Statistically, descriptive data of PK parameters will be computed. Relationships between such parameters as dose and AUC, volume of distribution, clearance, and others will be evaluated, but be preliminary due to the small sample size.
| d*ug/ml | Patients Dosed at 20mg/kg |
|---|---|
| Access Pharmacokinetics Through AUC0-∞ (Area Under Curve) | 422 ± 121 |
Evaluation of pharmacokinetics of veltuzumab and milatuzumab was performed for patients included in the trial. Statistically, descriptive data of PK parameters will be computed. Relationships between such parameters as dose and AUC, volume of distribution, clearance, and others will be evaluated, but be preliminary due to the small sample size.
| ug/ml | Patients Dosed at 20mg/kg |
|---|---|
| Access Pharmacokinetics Through Cmax | 480 ± 116 |
Patients will be monitored for the development of human anti-veltuzumab antibodies and human anti-milatuzumab antibodies (HAHA).
| patients | All Patients From Phase I and Phase II |
|---|---|
| anti-veltuzumab antibodies | 1 |
| anti-milatuzumab antibodies | 0 |
Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| All Patients From Phase I and Phase II | — | 3/35 (8.6%) | 35/35 (100%) |
| Event | All Patients From Phase I and Phase II |
|---|---|
| Infusion ReactionInjury, poisoning and procedural complications | 3/35 |
| Pulmonary embolusRespiratory, thoracic and mediastinal disorders | 2/35 |
| DeathGeneral disorders | 2/35 |
| PneumoniaRespiratory, thoracic and mediastinal disorders | 1/35 |
| BacteremiaBlood and lymphatic system disorders | 1/35 |
| Supraventricular tachycardiaCardiac disorders | 1/35 |
| FatigueGeneral disorders | 1/35 |
| HyperbilirubinemiaMetabolism and nutrition disorders | 1/35 |
| Fever without neutropeniaGeneral disorders | 1/35 |
| Event | All Patients From Phase I and Phase II |
|---|---|
| Infusion ReactionsInjury, poisoning and procedural complications | 21/35 |
| LymphopeniaBlood and lymphatic system disorders | 19/35 |
| LeukopeniaBlood and lymphatic system disorders | 8/35 |
| ThrombocytopeniaBlood and lymphatic system disorders | 7/35 |
| NeutropeniaBlood and lymphatic system disorders | 5/35 |
| AnemiaBlood and lymphatic system disorders | 5/35 |
| InfectionInfections and infestations | 5/35 |
| HyperglycemiaMetabolism and nutrition disorders | 4/35 |
| FatigueGeneral disorders | 3/35 |
| NauseaGastrointestinal disorders | 2/35 |
Patients with histologically confirmed B-cell NHL including marginal zone lymphoma, Waldenstrom's macroglobulinemia or lymphoplasmacytic lymphoma, follicular lymphoma, or mantle cell lymphoma by WHO criteria.
| Age, Continuous(years) | Phase I | Phase II | Total |
|---|---|---|---|
| Median | 65 (44 to 81) | 63 (39 to 82) | 63 (39 to 82) |
| Gender(Participants) | Phase I | Phase II | Total |
|---|---|---|---|
| Female | 5 | 7 | 12 |
| Male | 13 | 10 | 23 |
| Region of Enrollment(patients) | Phase I | Phase II | Total |
|---|---|---|---|
| United States | 18 | 17 | 35 |
Plan to share: No
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