A Phase I/Ib Study of the PD-1 Antibody Pembrolizumab in Combination With Ibrutinib in Relapsed/Refractory Non-Hodgkin's Lymphoma (NHL)
Overview
- Phase
- Phase 1
- Intervention
- Ibrutinib
- Conditions
- B-Cell Lymphoma, Unclassifiable, With Features Intermediate Between Diffuse Large B-Cell Lymphoma and Classical Hodgkin Lymphoma
- Sponsor
- Kami Maddocks
- Enrollment
- 2
- Locations
- 1
- Primary Endpoint
- Incidence of adverse events assessed using NCI CTCAE version 4
- Status
- Completed
- Last Updated
- 6 years ago
Overview
Brief Summary
This phase I/Ib trial studies the side effects and best dose of ibrutinib when given together with pembrolizumab and to see how well they work in treating patients with non-Hodgkin lymphoma that has come back or does not respond to treatment. Monoclonal antibodies, such as pembrolizumab, may interfere with the ability of cancer cells to grow and spread. Ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Given pembrolizumab and ibrutinib may work better in treating patients with non-Hodgkin lymphoma.
Detailed Description
PRIMARY OBJECTIVES: I. To determine the safety and tolerability of the combination of ibrutinib and pembrolizumab in patients with relapsed/refractory non-Hodgkin lymphoma (NHL). II. To determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of the combination of ibrutinib and pembrolizumab in patients with relapsed/refractory NHL. III. To evaluate the efficacy of the combination of ibrutinib and pembrolizumab in patients with relapsed/refractory NHL. SECONDARY OBJECTIVES: I. To determine the overall response rate (ORR), duration of response, progression-free survival and overall survival of the combination of ibrutinib and pembrolizumab in patients with relapsed/refractory NHL. TERTIARY OBJECTIVES: I. To explore the relationship between prognostic parameters including ki-67 staining, PD-1 staining and cell of origin (activated B-cell or ABC versus germinal center B-cell or GCB) with ORR to the combination of ibrutinib and pembrolizumab in patients with relapsed/refractory NHL. II. To determine relationship between gene mutations and resistance to therapy with the combination of ibrutinib and pembrolizumab in patients with relapsed/refractory NHL (BTK, PLC gamma 2, PD-1). III. To evaluate and monitor effects on B-, T-, and natural killer (NK)-cell function with the combination of ibrutinib and pembrolizumab in patients with relapsed/refractory NHL. OUTLINE: This is a phase I, dose-escalation study of ibrutinib followed by a phase Ib study. Patients receive ibrutinib orally (PO) daily on days 1-21 and pembrolizumab intravenously (IV) over 30 minutes on day 1. Treatment repeats every 21 days for up to 17 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up for 30 days, and then every 3 months for 2 years and every 6 months for 3 years.
Investigators
Kami Maddocks
Principal Investigator
Ohio State University Comprehensive Cancer Center
Eligibility Criteria
Inclusion Criteria
- •Histologically confirmed B-cell NHL with any of the following subtypes: diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), marginal zone lymphoma (MZL) and lymphoplasmacytic lymphoma/Waldenstrom's macroglobulinemia (LL/WM), Burkitt's lymphoma (BL); patients with histological transformation to DLBCL from indolent lymphoma, primary mediastinal lymphoma and grey zone lymphoma are eligible (Part 1)
- •Patients must have received at least one prior therapy; prior autologous stem cell transplant is permitted; patients with DLBCL who have not had prior high-dose therapy (HDT)/autologous stem cell transplant (ASCT) must be ineligible for transplant; prior ibrutinib is not permitted if patients have progressed on therapy (Part 1)
- •Patients with Waldenstrom's macroglobulinemia (WM) must meet the indications for treatment per the International Workshop on Waldenstrom's Macroglobulinemia (IWWM) (Part 1)
- •Histologically confirmed B-cell NHL (Part 2):
- •Group 1: with only de novo DLBCL,
- •Group 2: with only FL of grade 1, 2 or 3a
- •Group 3: with only MCL with t(11;14) or overexpression of cyclin D1
- •Group 4: all other NHL including MZL, LL, WM, BL, primary mediastinal B cell lymphoma (PMBCL), gray zone lymphoma (GZL) and patients with histological transformation to DLBCL from indolent lymphoma are eligible
- •Patients must have received at least one prior therapy; prior autologous stem cell transplant is permitted; patients with DLBCL who have not had prior HDT/ASCT must be ineligible for transplant; prior ibrutinib is not permitted if patients have progressed on therapy (Part 2)
- •Patients with Waldenstrom's macroglobulinemia (WM) must meet the indications for treatment per the International Workshop on Waldenstrom's Macroglobulinemia (IWWM) (Part 2)
Exclusion Criteria
- •Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment
- •Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment; subjects may use topical or inhaled corticosteroids or low-dose steroids (=\< 10 mg of prednisone or equivalent per day) as therapy for comorbid conditions; during study participation, subjects may receive systemic or enteric corticosteroids as needed for treatment-emergent comorbid conditions
- •Has a known history of active TB (Bacillus tuberculosis)
- •Hypersensitivity to pembrolizumab or ibrutinib or any of their excipients
- •Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study day 1 or who has not recovered (i.e., =\< grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier
- •Has had prior chemotherapy or radiation therapy within 2 weeks prior to study day 1 or who has not recovered (i.e., =\< grade 1 or at baseline) from adverse events due to a previously administered agent
- •Note: subjects with =\< grade 2 neuropathy are an exception to this criterion and may qualify for the study
- •Note: if subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy; patients must be 4 weeks out from major procedures and 2 weeks out from minor procedures
- •Has a known additional malignancy that is progressing or requires active treatment; exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer
- •Has known active central nervous system (CNS) lymphoma
Arms & Interventions
Arm 1
Intervention: Ibrutinib
Arm 1
Intervention: Laboratory Biomarker Analysis
Arm 1
Intervention: Pembrolizumab
Outcomes
Primary Outcomes
Incidence of adverse events assessed using NCI CTCAE version 4
Time Frame: Up to 5 years
Summarized based on severity and perceived attribution to study treatment. Will be assessed and tabulated by dose level.
MTD defined as the dose level at which no more than one of 6 patients experiences a dose-limiting toxicity assessed using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4
Time Frame: Up to 21 days
Secondary Outcomes
- ORR(Up to 5 years)
- Complete response rates(Up to 5 years)
- Overall survival(From study entry to the time of death due to any cause, assessed up to 5 years)
- Progressive-free survival(From study entry to the time of progression and/or death, assessed up to 5 years)