Phase 1/2 study of intratumoral G100 (TLR4 agonist) with or without pembrolizumab in follicular lymphoma

Abstract AQ4N is a prodrug which is selectively bioreduced by cytochrome P450 to AQ4, a potent DNA intercalator and topoisomerase II inhibitor. Preclinical studies demonstrate AQ4N selectively targets lymphoblastoid cell lines and hypoxic tumors. This study assessed the maximum tolerated dose (MTD), and pharmacokinetics (PK) of repeated dosing of AQ4N in patients (pts) with lymphoid malignancies. AQ4N was administered IV on Day 1 of a 21 day cycle to cohorts of at least three pts at doses of 400, 800, or 1200 mg/m2 for a maximum of 8 cycles. The dose was escalated as long as <33% of pts did not experience a dose limiting toxicity (DLT). 11 pts were enrolled with 3 pts treated at 400 mg/m2 and 4 pts treated at 800 and 1200 mg/m2 each. No pts experienced a DLT and no clinical MTD was identified. No further dose escalation was investigated due to reaching known maximum AQ4N solution solubility. The most common related adverse events (AE) observed were expected transient skin discoloration (100%), transient chromaturia (36%) and lymphopenia (27%), as well as fatigue (27%) and nausea (27%). AEs were primarily mild (Grade 1–2) with the exception of Grade 3 lymphopenias (n=3) and Grade 3 neutopenia (n=1) events. No dose reductions or dose delays resulted from these hematologic decreases. 6 pts experienced at least one serious AE, including: pneumonia, staph aureus bacteremia, acute respiratory distress syndrome (ARDS), dyspnea, and pleural effusion, none of which were attributed to AQ4N. The PK was linear over all doses studied. At 1200 mg/m2 (n=4), the Day 1 AQ4N Cmax was 122.3 ± 13.1 μg/mL, AUC0–∞ was 340.8 ± 68.7 μg·h/mL, and T1/2 was 3.2 h (range 2.8 to 4.1 h). One pt with follicular lymphoma dosed at 1200 mg/m2 had a partial response after the 4th cycle using the NHL standardized response criteria. The pt went on to complete all 8 cycles and to date remains in partial response. The bioreductive prodrug, AQ4N, is well-tolerated when administered on a repeated 21-day schedule at doses up to and including 1200 mg/m2. Further dose escalation was precluded since the known maximum solubility of AQ4N was reached. Blood levels of AQ4N achieved in this study appear to be within the range of potentially therapeutic levels of the active drug, AQ4, as seen in previous preclinical and clinical studies of solid tumors (Harris PA et al, 2006; Albertella MR et al., 2006). Preliminary evidence of anti-tumor activity was seen in one pt with follicular lymphoma. Further clinical studies of AQ4N administered both as a monotherapy and in combination with chemo- and radiation therapy are planned in B-cell neoplasms and solid tumor malignancies.

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Weekly Treatment with a Combination of Bendamustine and Bortezomib in Relapsed or Refractory Indolent Non-Hodgkin’s Lymphoma: A Single- Center Phase 1/2 Study.

Blood ◽

10.1182/blood.v112.11.1574.1574 ◽

2008 ◽

Vol 112 (11) ◽

pp. 1574-1574 ◽

Cited By ~ 3

Author(s):

Peter R Moosmann ◽

Marc Heizmann ◽

Nina Kotrubczik ◽

Mario Bargetzi ◽

Martin Wernli

Keyword(s):

Adverse Events ◽

Follicular Lymphoma ◽

Mantle Cell Lymphoma ◽

Hodgkin’S Lymphoma ◽

Cell Lymphoma ◽

Phase 1 ◽

Hodgkin's Lymphoma ◽

Non Hodgkin’S Lymphoma ◽

Non Hodgkin's Lymphoma ◽

Mantle Cell

Abstract Besides its established role in the treatment of patients with multiple myeloma, the proteasome inhibitor bortezomib is active in patients with a variety of indolent non-Hodgkin’s lymphomas, notably mantle cell lymphoma and follicular lymphoma. Bendamustine was originally designed as a bifunctional anticancer compound combining an alkylating and an antimetabolite function. It has strong efficacy in non-Hodgkin’s lymphoma and multiple myeloma, and apparently low cross-resistance with other alkylating agents. This open label, single-center phase 1/2 study evaluated a weekly combination of bortezomib and bendamustine in patients with relapsed or refractory indolent non-Hodgkin’s lymphoma. The primary endpoint was to define the maximal tolerated dose (MTD). Secondary endpoints were tolerability and response. On days 1, 8, 15, and 22 of a 35-day cycle, patients received intravenous bolus bortezomib 1.6 mg/m2 for a maximum of 3 cycles. Bendamustine was administered as 30-min. intravenous infusion on days 1, 8, and 15. Dose escalation was started at a dose of 60 mg/m2 bendamustine. Response was assessed at the end of study treatment. Four patients entering the first dose level showed no dose-limiting toxicity (DLT). Thereupon, bendamustine dosage was increased to 80 mg/m2. In 3 out of 5 patients, DLT was observed. Dose-limiting adverse events were grade 3 diarrhea with dehydration, fatigue, and grade 4 thrombocytopenia, respectively. Adverse events with an overall incidence of ≥20% were diarrhea, nausea, vomiting, thrombocytopenia, and fatigue. There were no infectious or dose-limiting neurological adverse events. The 9 patients (7 females) in the phase 1 part of this trial, 5 with relapsed, 4 with refractory stage III (n=2) or stage IV (n=7) disease, received a median of 2 treatment cycles (range 2–3). Median age was 71 yrs (range 55–85). Detailed histological diagnoses were mantle cell lymphoma (n=4), follicular lymphoma (n=4), and Waldenstroem’s macroglobulinemia (n=1). All patients were pretreated (median 3 lines of treatment, range 2–8). Prior treatments comprised rituximab (n=7), anthracyclines (n=4), ibritumomab tiuxetan (n=2), bortezomib (n=2), and autologous stem cell transplantation (n=1). The reasons for not completing the planned 3 treatment cycles were DLT (n=2), and disease progression (n=3). As best response, partial remission was achieved in 6 patients, while disease progressed in 3 patients. Among the different types of lymphoma, partial remissions were observed in all 4 mantle cell lymphoma patients, 1 out of 4 follicular lymphoma patients, and in the Waldenstroem’s macroglobulinemia patient. The trial’s phase 2 part is currently ongoing. In conclusion, weekly bortezomib and bendamustine (1.6 mg/m2 d1, 8, 15, & 22 and 60 mg/m2 d1, 8, & 15 q5w, respectively) was found to have acceptable toxicity. Moreover, this study demonstrates initial evidence of efficacy of the combination in heavily pretreated patients with indolent non-Hodgkin’s lymphoma, particularly mantle cell lymphoma.

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Population Pharmacokinetics Study of a New Humanized Anti-CD20 Monoclonal Antibody AME-133v (LY2469298) in Patients with Previously Treated Follicular Lymphoma (FL)

Blood ◽

10.1182/blood.v118.21.4982.4982 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4982-4982

Author(s):

Damien Cronier ◽

David Radtke ◽

Susan P. Carpenter ◽

James Wooldridge

Keyword(s):

Monoclonal Antibody ◽

Follicular Lymphoma ◽

Dose Group ◽

Limit Of Detection ◽

Phase 1 ◽

Elimination Rate ◽

Employment Equity ◽

Mixed Effect ◽

Previously Treated ◽

Equity Ownership

Abstract Abstract 4982 Background: AME-133v is a humanized monoclonal antibody that was engineered to have increased affinity to CD20 and mediate antibody-dependent cell-mediated cytotoxicity (ADCC) better than rituximab in vitro. The safety, pharmacokinetics (PK) and preliminary efficacy of AME-133v were assessed in a Phase 1/2 clinical trial in patients with previously treated follicular lymphoma (FL). The objective of this study is to characterize the pharmacokinetics (PK) of AME-133v in the target patient population. Methods: 5 dose levels of AME-133v (2, 7.5, 30, 100, and 375 mg/m2) were tested in a total of 67 patients with previously treated CD20+ FL. AME-133v was administered intravenously in four weekly infusions. Blood samples were obtained pre-dose and 1, 3–5 days after infusion 1, pre-dose and post-dose during infusions 2, 3 and 4, and 1, 5 and 9 weeks after infusion 4. The PK database (399 data points) collected from the patients was analyzed by using the nonlinear mixed-effect model (NONMEM) program. A number of covariates including demographic characteristics and the FcγRIIIa receptor genotype were evaluated for their influence on the AME-133v population PK parameters. Results: Owing to serum concentrations values falling below the limit of detection, the 2 mg/m2 dose group was not included in the analysis. The basic model selected was a two-compartment pharmacokinetic model with first-order elimination. However, a different typical value had to be determined for CL in each dose group. The typical values of V1, Q and V2 were 2.99 L, 0.94 L/day, and 3.31 L, respectively. The typical value for CL was 0.70, 0.53, 0.26, 0.27 L/day-1 for 7.5, 30, 100 and 375 mg/m2, respectively, which indicates a linearization of the elimination rate of AME-133v at doses of 100 mg/m2 and above. Inter-individual variability was moderate to high with CVs of 45.9, 34.1 and 50.0% on CL, V1 and V2, respectively. The only covariate found to influence the PK of AME-133v was BSA which explained 9.6% of the variability observed on V1. The form of the FcγRIIIa receptor was not found to have a significant effect on the PK of AME-133v. Conclusions: The PK of AME-133v were best described by a 2-compartment model. Clearance was found to be dose-dependent with a linearization of the elimination rate at doses of 100 mg/m2 and above. BSA has a statistically significant influence on V1 whereas the FcγRIIIa genotype does not seem to influence the disposition of AME-133v. Disclosures: Cronier: Eli Lilly and Comany: Employment, Equity Ownership. Off Label Use: AME-133v is an investigational agent. Radtke:Eli Lilly and Comany: Employment, Equity Ownership. Wooldridge:Eli Lilly and Company: Employment, Equity Ownership.

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Phase 1 clinical trial of the PI3Kδ inhibitor YY-20394 in patients with B-cell hematological malignancies

Journal of Hematology & Oncology ◽

10.1186/s13045-021-01140-z ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Bo Jiang ◽

Junyuan Qi ◽

Yuqin Song ◽

Zengjun Li ◽

Meifeng Tu ◽

...

Keyword(s):

Follicular Lymphoma ◽

B Cell ◽

Phase 1 ◽

Objective Response ◽

Human Study ◽

Progression Free Survival ◽

Maximum Tolerated Dose ◽

Lymphocytic Leukemia ◽

Pharmacokinetic Parameters ◽

Durable Response

AbstractYY-20394, an oral phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitor, was investigated in a first-in-human study of patients with relapsed or refractory B-cell malignancies. During dose escalation, 25 patients received 20–200 mg of YY-20394 daily. The primary outcome measures were tolerability and dose-limiting toxicity (DLT). The secondary outcomes were pharmacokinetic parameters, progression-free survival (PFS) and the objective response rate (ORR). Since no patients experienced DLT, the maximum tolerated dose (MTD) was not reached. The majority (≥ 5%) of drug-related adverse events were ≥ grade III, being neutropenia (44.0%), pneumonia (16.0%), hyperuricemia (12.0%), lymphocythemia (8.0%), leukopenia (8.0%) and pneumonitis (8.0%). The overall ORR was 64.0% (95% confidence interval (CI): 45.2, 82.8%) including 5 patients with complete remission (CR), 11 with partial remission (PR), 2 with stable disease (SD) and 7 with progressive disease (PD), while the disease control rate (DCR) was 72.0% (95% CI: 54.4, 89.6%). The ORR of 10 patients with follicular lymphoma was 90%. The median PFS time was 255 days. One PR patient with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) who received 40 mg q.d. had a durable response of around 36 months. The median PFS time of 10 patients with follicular lymphoma was 300 days. A recommended phase 2 dose of 80 mg q.d. was established. Considering that YY-20394 was well-tolerated with promising preliminary efficacy, further development is warranted.Trial registration clinicaltrials.gov, NCT03757000, retrospectively registered, November 28, 2018, https://clinicaltrials.gov/ct2/show/NCT03757000?term=NCT03757000&draw=2&rank=1.

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Phase 1 Clinical Study of Atacicept in Patients with Relapsed and Refractory B-Cell Lymphoma.

Blood ◽

10.1182/blood.v108.11.2722.2722 ◽

2006 ◽

Vol 108 (11) ◽

pp. 2722-2722 ◽

Cited By ~ 1

Author(s):

Stephen Ansell ◽

Thomas E. Witzig ◽

Anne Novak ◽

David James ◽

Luis Porrata ◽

...

Keyword(s):

Follicular Lymphoma ◽

B Cell ◽

Disease Progression ◽

Stable Disease ◽

Cell Lymphoma ◽

Phase 1 ◽

B Cell Lymphoma ◽

B Cell Malignancies ◽

Mantle Cell ◽

Heavily Pretreated

Abstract Background: Atacicept (TACI-Ig) is a recombinant fusion protein that inhibits BLyS (B lymphocyte stimulator) and APRIL (a proliferation-inducing ligand), cytokines that are involved in B-cell homeostasis and immunoglobulin (Ig) expression and are overexpressed in B-cell malignancies. In vitro, atacicept decreases the survival of lymphoma cells and in vivo, atacicept decreases serum immunoglobulin levels. Based on its effects on B cells, atacicept may offer a novel treatment for B-cell malignancies. Methods: A Phase 1, open-label, dose-escalation study of atacicept in patients with relapsed or refractory B-cell lymphoma was performed. Atacicept was administered subcutaneously for 5 weeks in single weekly doses of 2, 4, 7, or 10 mg/kg to sequential patient cohorts. After 8 weeks, patients with responding or stable disease were eligible for treatment on an extension study at the dose previously received for up to 24 weeks or until disease progression. The primary study objective was evaluation of overall safety and the maximum tolerated dose. Pharmacokinetics and biomarkers were also investigated. Results: As of July 2006, 15 patients with relapsed and refractory diffuse large B-cell lymphoma (7), follicular lymphoma (4), small lymphocytic lymphoma/chronic lymphocytic leukemia (2), and mantle-cell lymphoma (2) received 2, 4, or 7 mg/kg atacicept (4 patients per dose cohort) or 10 mg/kg atacicept (3 patients). All patients were heavily pretreated (median number of previous treatments was 5, range 1–10) and 4 patients had previously received a stem cell transplant. All patients completed study treatment (5 doses), except 2 who withdrew due to disease progression after receiving 2 and 4 doses. Atacicept was well tolerated at all doses. The most common adverse events (AEs) that occurred in ≥20% of patients were fatigue (47%) and injection site bruising (20%). Three AEs with ≥ grade 3 severity were reported for 1 patient including pain in jaw, gastrointestinal hemorrhage, and sepsis; all were considered unrelated to atacicept. Four SAEs considered unrelated to atacicept were reported for 2 patients who withdrew due to disease progression. Pharmacokinetic results were nonlinear and consistent with observations in other indications. Five weekly doses produced low to moderate accumulation of free total atacicept and atacicept/BLyS complex in serum. IgA, IgG, and IgM concentrations decreased in a dose-related pattern with a mean decrease of 15–40% from baseline after 4 weeks of atacicept. Peripheral B-cell numbers were variable and were difficult to evaluate due to low B-cell values at baseline in the majority of patients. At the 8-week evaluation, no objective responses were observed. Two patients had stable disease (1 with mantle cell lymphoma and 1 with follicular lymphoma) at 8 weeks, entered the extension study, and received additional doses of atacicept with no safety or tolerability concerns. Both patients however later discontinued treatment due to disease progression. Conclusion: Atacicept at doses of up to 10 mg/kg was well tolerated and demonstrated biological activity by decreasing Ig concentrations in this heavily pretreated cohort of patients with refractory B-cell lymphoma, although tumor responses were not observed.

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Phase 1 trial of rituximab, lenalidomide, and ibrutinib in previously untreated follicular lymphoma: Alliance A051103

Blood ◽

10.1182/blood-2016-06-718106 ◽

2016 ◽

Vol 128 (21) ◽

pp. 2510-2516 ◽

Cited By ~ 35

Author(s):

Chaitra S. Ujjani ◽

Sin-Ho Jung ◽

Brandelyn Pitcher ◽

Peter Martin ◽

Steven I. Park ◽

...

Keyword(s):

Follicular Lymphoma ◽

Patient Population ◽

Phase 1 ◽

Phase 1 Trial ◽

Key Points ◽

High Incidence

Key Points The combination of rituximab, lenalidomide, and ibrutinib is associated with a high incidence of rash in follicular lymphoma (all grades 82%). Efficacy of the triplet appears similar to rituximab-lenalidomide in the same patient population.

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Efficacy and safety results from CheckMate 140, a phase 2 study of nivolumab for relapsed/refractory follicular lymphoma

Blood ◽

10.1182/blood.2019004753 ◽

2020 ◽

Cited By ~ 3

Author(s):

Philippe Armand ◽

Ann MH Janssens ◽

Giuseppe Gritti ◽

John Radford ◽

John M Timmerman ◽

...

Keyword(s):

Follicular Lymphoma ◽

Phase 1 ◽

Objective Response ◽

Phase 2 ◽

Efficacy And Safety ◽

Tumor Associated Macrophage ◽

Phase 2 Trial ◽

Programmed Death ◽

Phase 2 Study ◽

Programmed Death 1

Nivolumab, an anti-programmed death-1 (PD-1) monoclonal antibody, showed promising activity in relapsed or refractory (R/R) follicular lymphoma (FL) in a phase 1 study. We conducted a phase 2 trial to evaluate further its efficacy and safety in patients with R/R FL and to explore biomarkers of response. Patients with R/R FL and at least two prior lines of therapy, each containing a CD20 antibody or an alkylating agent, were treated with nivolumab 3 mg/kg every 2 weeks. The primary endpoint was objective response rate (ORR) assessed by independent radiologic review committee. Biomarker analyses included gene expression profiling and multiplex immunofluorescence studies of pretreatment tumor samples. A total of 92 patients were treated. After a minimum follow-up of 12 months, ORR was 4% (4/92). Median PFS was 2.2 months (95% confidence interval [CI], 1.9-3.6). Median DOR was 11 months (95% CI, 8-14). Exploratory analyses suggested that responders had significantly higher proportion of CD3+ T cells in the tumor microenvironment than non-responders, but no significant differences in PD-1 or PD-L1 expression were observed. High expression of a set of tumor-associated macrophage genes was associated with reduced PFS (hazard ratio, 3.28; 95% CI, 1.76-6.11; P = .001). The safety profile was consistent with previous reports of nivolumab. In conclusion, nivolumab monotherapy was associated with very limited activity in patients with R/R FL. Better understanding of the immune biology of this disease may facilitate the development of effective checkpoint-based strategies. This trial was registered at www.clinicaltrials.gov as #NCT02038946.

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High rate of durable complete remission in follicular lymphoma after CD19 CAR-T cell immunotherapy

Blood ◽

10.1182/blood.2019000905 ◽

2019 ◽

Vol 134 (7) ◽

pp. 636-640 ◽

Cited By ~ 38

Author(s):

Alexandre V. Hirayama ◽

Jordan Gauthier ◽

Kevin A. Hay ◽

Jenna M. Voutsinas ◽

Qian Wu ◽

...

Keyword(s):

T Cell ◽

Complete Remission ◽

Follicular Lymphoma ◽

Phase 1 ◽

High Rate ◽

Car T Cell ◽

Cell Immunotherapy ◽

Car T ◽

T Cell Immunotherapy

Abstract Patients with follicular lymphoma (FL) with early relapse after initial chemoimmunotherapy, refractory disease, or histologic transformation (tFL) have limited progression-free and overall survival. We report efficacy and long-term follow-up of 21 patients with relapsed/refractory (R/R) FL (n = 8) and tFL (n = 13) treated on a phase 1/2 clinical trial with cyclophosphamide and fludarabine lymphodepletion followed by infusion of 2 × 106 CD19-directed chimeric antigen receptor–modified T (CAR-T) cells per kilogram. The complete remission (CR) rates by the Lugano criteria were 88% and 46% for patients with FL and tFL, respectively. All patients with FL who achieved CR remained in remission at a median follow-up of 24 months. The median duration of response for patients with tFL was 10.2 months at a median follow-up of 38 months. Cytokine release syndrome occurred in 50% and 39%, and neurotoxicity in 50% and 23% of patients with FL and tFL, respectively, with no severe adverse events (grade ≥3). No significant differences in CAR-T cell in vivo expansion/persistence were observed between FL and tFL patients. CD19 CAR-T cell immunotherapy is highly effective in adults with clinically aggressive R/R FL with or without transformation, with durable remission in a high proportion of FL patients. This trial was registered at clinicaltrials.gov as #NCT01865617.

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