Clinical trial NCT01992653: A Study of Polatuzumab Vedotin in Combination With Rituximab or Obinutuzumab, Cyclophosphamide, Doxorubicin, and Prednisone in Participants With B-Cell Non-Hodgkin's Lymphoma
Official title: A Phase Ib/II Study Evaluating the Safety, Tolerability and Anti-Tumor Activity of Polatuzumab Vedotin (DCDS4501A) in Combination With Rituximab or Obinutuzumab, Cyclophosphamide, Doxorubicin, and Prednisone in Patients With B-Cell Non-Hodgkin's Lymphoma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Lymphoma, Non Hodgkin
Lead sponsor: Genentech, Inc.
Sponsor class: INDUSTRY
First posted: 2013-11-25
Enrollment: 85
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This multicenter, open-label, dose-escalation study will evaluate the safety, tolerability, pharmacokinetics, and anti-tumor activity of polatuzumab vedotin in combination with rituximab or obinutuzumab, cyclophosphamide, doxorubicin, and prednisone (CHP chemotherapy) in participants with non-Hodgkin's lymphoma (NHL). Participants will receive escalating doses of polatuzumab vedotin intravenously (IV) every 3 weeks in combination with standard doses of rituximab plus CHP chemotherapy (R-CHP) or obinutuzumab plus CHP chemotherapy (G-CHP). Participants will be treated for a total of six or eight cycles in accordance with local institutional practice. Two parallel treatment arms will explore doses of polatuzumab vedotin in combination with R-CHP or G-CHP. The maximum tolerated dose (MTD) or recommended Phase 2 dose (RP2D) of polatuzumab vedotin in combination with R-CHP will be identified before it is combined with G-CHP. Once the MTD or RP2D is determined, polatuzumab vedotin will be dosed at MTD or RP2D -1 in combination with G-CHP to start the dose escalation of this combination.


Eligibility criteria: Inclusion Criteria:

All Participants:

* At least one bi-dimensionally measurable lesion, defined as greater than (\>) 1.5 centimeters (cm) in its longest dimension
* Life expectancy of at least 24 weeks
* Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
* Adequate hematologic function (unless inadequate function is due to underlying disease, as established by extensive bone marrow involvement or is due to hypersplenism secondary to the involvement of the spleen by lymphoma per the investigator)
* Agreement to use highly effective contraception measures. Women of childbearing potential must agree to remain abstinent or use contraceptive measures that result in a failure rate of \<1 percent (%) per year during the treatment period and for at least 12 months for R-CHP arm or for at least 18 months for G-CHP arm after the last dose of study drug. Men must agree to remain abstinent or to use a condom plus an additional contraceptive method that together result in a failure rate of \<1% per year during the treatment period and for at least 5 months after the last dose of study drug

Dose-Escalation Portion of the Study:

* Histologically confirmed B-cell NHL: Participants with newly diagnosed B-cell NHL or relapsed/refractory B-cell NHL are eligible
* No more than one prior systemic treatment regimen for B-cell NHL (single agent anti-cluster of differentiation \[CD\] 20 monoclonal antibody therapy will not be counted as a prior treatment regimen)
* No prior treatment with anthracyclines

Expansion Portion of the Study:

* Previously untreated participants with diffuse large B-cell lymphoma (DLBCL)
* International Prognostic Index (IPI) score of 2-5

Exclusion Criteria:

Dose-Escalation Portion of the Study:

* Diagnosis of primary mediastinal DLBCL

Expansion Portion of the Study:

* Participants with transformed lymphoma
* Prior therapy for NHL

All Participants:

* Prior stem cell transplant
* History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies or known sensitivity or allergy to murine products
* Contraindication to receive any of the individual components of R-CHP or G-CHP
* Current Grade greater than (\>) 1 peripheral neuropathy
* Ongoing corticosteroid use of \>30 milligrams per day (mg/day) of prednisone/prednisolone or equivalent. Participants receiving corticosteroid treatment with less than or equal to (\</=) 30 mg/day of prednisone/prednisolone or equivalent must be documented to be on a stable dose of at least 4 weeks' duration before Cycle 1 Day 1
* Primary central nervous system (CNS) lymphoma
* Vaccination with live vaccines within 6 months before Cycle 1 Day 1
* History of other malignancy that could affect compliance with the protocol or interpretation of results. Participants with a history of curatively treated basal or squamous cell carcinoma or melanoma of the skin or in situ carcinoma of the cervix are eligible. Participants with a malignancy that has been treated with surgery alone with curative intent will also be excluded unless the malignancy has been in documented remission without treatment for greater than or equal to (\</=) 5 years before enrollment
* Evidence of significant, uncontrolled concomitant diseases, including renal disease that would preclude chemotherapy administration, or pulmonary disease (including obstructive pulmonary disease and history of bronchospasm)
* Significant cardiovascular disease (such as New York Heart Association Class III or IV cardiac disease, congestive heart failure, myocardial infarction within the previous 6 months, unstable arrhythmias, or unstable angina) or significant pulmonary disease
* Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) at study enrollment or any major episode of infection requiring treatment with IV antibiotics or hospitalization (relating to the completion of the course of antibiotics) within 4 weeks before Cycle 1 Day 1
* Clinically significant history of liver disease, including viral or other hepatitis, current alcohol abuse, or cirrhosis
* Positive for hepatitis B or hepatitis C infection
* Prior radiotherapy to the mediastinal/pericardial region
* Pregnant or lactating women
* Recent major surgery within 6 weeks before the start of Cycle 1 Day 1

Primary outcomes:
measure: Number of Participants With Adverse Events in Diffuse Large B-Cell Lymphoma (DLBCL) Population
timeFrame: Baseline up to 5 years
measure: Number of Participants With Adverse Events in Non-DLBCL Population
timeFrame: Baseline up to 5 years
measure: Number of Participants With Dose Limiting Toxicities (DLTs) in DLBCL Population
timeFrame: Cycle (Cy) 1 Day 1 (D1) to Cy 2 D1 (cycle length=21 days)
measure: Number of Participants With DLTs in Non-DLBCL Population
timeFrame: Cycle (Cy) 1 Day 1 (D1) to Cy 2 D1 (cycle length=21 days)
Secondary outcomes:
measure: Percentage of Participants With Objective Response (CR or Partial Response [PR]), as Assessed by Investigator Using Cheson Criteria for DLBCL Population
timeFrame: At the end of treatment (Month 6)
measure: Percentage of Participants With Objective Response (CR or Partial Response [PR]), as Assessed by Investigator Using Cheson Criteria for Non-DLBCL Population
timeFrame: At the end of treatment (Month 6)
measure: Number of Participants With Anti-Polatuzumab Vedotin Antibodies
timeFrame: Baseline up to Month 9 (assessed prior to polatuzumab vedotin infusion [0 hour; Hr] on Day 2 [D2] of Cy 1 and 2, D1 of Cy 4, treatment completion/early termination [Month 6], and at 3 months post-treatment [Month 9]; cycle length=21 days)
measure: Number of Participants With Anti-Obinutuzumab Antibodies
timeFrame: Baseline up to Month 9 (assessed prior to obinutuzumab infusion [0 Hr] on D1 of Cy 1, 2, 4 and at 3 months post-treatment [Month 9]; cycle length=21 days)
measure: Area Under the Concentration-Time Curve (AUC) of Polatuzumab Vedotin
timeFrame: Pre-polatuzumab vedotin infusion (Hr 0), 30 minutes (min) post-infusion (infusion time=30-90 min) on D 2 of Cy 1, 2 & D1 of Cy 3, 4; Cy 1 Days 8 & 15; Cy 3 Day 8; at end of treatment (Month 6), at Month 3 follow-up (Month 9) (cycle length=21 days)
measure: Maximum Concentration (Cmax) of Polatuzumab Vedotin
timeFrame: Pre-polatuzumab vedotin infusion (Hr 0), 30 min post-infusion (infusion time=30-90 min) on D 2 of Cy 1, 2 & D1 of Cy 3, 4; Cy 1 Days 8 & 15; Cy 3 Day 8; at end of treatment (Month 6), at Month 3 follow-up (Month 9) (cycle length=21 days)
measure: Clearance (CL) of Polatuzumab Vedotin
timeFrame: Pre-polatuzumab vedotin infusion (Hr 0), 30 min post-infusion (infusion time=30-90 min) on D 2 of Cy 1, 2 & D1 of Cy 3, 4; Cy 1 Days 8 & 15; Cy 3 Day 8; at end of treatment (Month 6), at Month 3 follow-up (Month 9) (cycle length=21 days)
measure: Terminal Half-Life (t1/2) of Polatuzumab Vedotin
timeFrame: Pre-polatuzumab vedotin infusion (Hr 0), 30 min post-infusion (infusion time=30-90 min) on D 2 of Cy 1, 2 & D1 of Cy 3, 4; Cy 1 Days 8 & 15; Cy 3 Day 8; at end of treatment (Month 6), at Month 3 follow-up (Month 9) (cycle length=21 days)
measure: Steady-State Volume of Distribution (Vss) of Polatuzumab Vedotin
timeFrame: Pre-polatuzumab vedotin infusion (Hr 0), 30 min post-infusion (infusion time=30-90 min) on D 2 of Cy 1, 2 & D1 of Cy 3, 4; Cy 1 Days 8 & 15; Cy 3 Day 8; at end of treatment (Month 6), at Month 3 follow-up (Month 9) (cycle length=21 days)
measure: Plasma Levels of Cyclophosphamide
timeFrame: End of cyclophosphamide infusion (infusion time=1-24 Hr), 3 and 23 hours post end of cyclophosphamide infusion on D1 of Cy 1 and 3 (cycle length=21 days)
measure: Plasma Levels of Doxorubicin
timeFrame: 2, 24 hours post end of doxorubicin infusion (infusion time=15 min) on D1 of Cy 1 and 3 (cycle length=21 days)
measure: Peripheral Neuropathy Symptom Severity: Therapy-Induced Neuropathy Assessment Scale (TINAS) Overall Neuropathy Severity Score
timeFrame: Weekly up to Month 6 (22 weeks). TINAS data were collected daily, though for the analysis purpose for each participant, only the first record of each week was selected.
measure: Peripheral Neuropathy Symptom Interference: TINAS Numbness/Tingling Item Score
timeFrame: Weekly up to Month 6 (22 weeks). TINAS data were collected daily, though for the analysis purpose for each participant, only the first record of each week was selected.
measure: Duration of Response, as Assessed by Investigator Using Cheson Criteria for DLBCL Population
timeFrame: Screening up to disease progression or death, whichever occurs first (up to approximately 2.75 years)
measure: Duration of Response, as Assessed by Investigator Using Cheson Criteria for Non-DLBCL Population
timeFrame: Screening up to disease progression or death, whichever occurs first (up to approximately 2.75 years)
measure: Progression Free Survival, as Assessed by Investigator Using Cheson Criteria for DLBCL Population
timeFrame: Screening up to disease progression or death, whichever occurs first (up to approximately 2.75 years)
measure: Progression Free Survival, as Assessed by Investigator Using Cheson Criteria for Non-DLBCL Population
timeFrame: Screening up to disease progression or death, whichever occurs first (up to approximately 2.75 years)
measure: Event Free Survival, as Assessed by Investigator Using Cheson Criteria for DLBCL Population
timeFrame: Screening up to disease progression or death, whichever occurs first (up to approximately 2.75 years)
measure: Event Free Survival, as Assessed by Investigator Using Cheson Criteria for Non-DLBCL Population
timeFrame: Screening up to disease progression or death, whichever occurs first (up to approximately 2.75 years)
measure: Relative Dose Intensity of Polatuzumab Vedotin (Ratio of the Amount of Drug Actually Administered to the Amount Planned) for DLBCL Population
timeFrame: 6 months
measure: Relative Dose Intensity of Polatuzumab Vedotin (Ratio of the Amount of Drug Actually Administered to the Amount Planned) for Non-DLBCL Population
timeFrame: 6 months
measure: Overall Survival for DLBCL Population
timeFrame: Screening up to death due to any cause (up to approximately 6 years)
measure: Overall Survival for Non-DLBCL Population
timeFrame: Screening up to death due to any cause (up to approximately 6 years)
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: The University of Alabama at Birmingham
state: Alabama
city: Greeley
country: United States
facility: Banner MD Anderson Cancer Center
state: Colorado
city: Saint Louis
country: United States
facility: Washington University; Pediatrics
state: Missouri
city: Portland
country: United States
facility: Northwest Cancer Specialists
state: Oregon
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Springfield
country: United States
facility: Willamette Valley Clinical Studies; Cancer Institute
state: Oregon
city: Roanoke
country: United States
facility: Blue Ridge Cancer Care
state: Virginia
city: Creteil
country: France
facility: Hopital Henri Mondor, Unite Hemopathies lymphoides
city: Lille
country: France
facility: Hopital Claude Huriez - CHU Lille; Service des maladies du sang
city: Pierre Benite
country: France
facility: Centre Hospitalier Lyon Sud; Hematolgie
city: Rouen
country: France
facility: Centre Henri Becquerel; Hematologie
Study officials:
affiliation: Genentech, Inc.
name: Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Shi R, Lu T, Ku G, Ding H, Saito T, Gibiansky L, Agarwal P, Li X, Jin JY, Girish S, Miles D, Li C, Lu D. Asian race and origin have no clinically meaningful effects on polatuzumab vedotin pharmacokinetics in patients with relapsed/refractory B-cell non-Hodgkin lymphoma. Cancer Chemother Pharmacol. 2020 Sep;86(3):347-359. doi: 10.1007/s00280-020-04119-8. Epub 2020 Aug 8.
citation: Tilly H, Morschhauser F, Bartlett NL, Mehta A, Salles G, Haioun C, Munoz J, Chen AI, Kolibaba K, Lu D, Yan M, Penuel E, Hirata J, Lee C, Sharman JP. Polatuzumab vedotin in combination with immunochemotherapy in patients with previously untreated diffuse large B-cell lymphoma: an open-label, non-randomised, phase 1b-2 study. Lancet Oncol. 2019 Jul;20(7):998-1010. doi: 10.1016/S1470-2045(19)30091-9. Epub 2019 May 14.