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

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.

scholarly journals The phase 3 DUO trial: duvelisib vs ofatumumab in relapsed and refractory CLL/SLL

Blood ◽  
2018 ◽  
Vol 132 (23) ◽  
pp. 2446-2455 ◽  
Author(s):  
Ian W. Flinn ◽  
Peter Hillmen ◽  
Marco Montillo ◽  
Zsolt Nagy ◽  
Árpád Illés ◽  
...  
Keyword(s):  
B Cell ◽  
Phase 1 ◽  
Randomized Study ◽  
Progression Free Survival ◽  
Hematologic Malignancies ◽  
Lymphocytic Leukemia ◽  
Primary Study ◽  
Effective Treatment Option ◽  
Phase 3 ◽  
Dual Inhibitor

Abstract Duvelisib (also known as IPI-145) is an oral, dual inhibitor of phosphatidylinositol 3-kinase δ and γ (PI3K-δ,γ) being developed for treatment of hematologic malignancies. PI3K-δ,γ signaling can promote B-cell proliferation and survival in clonal B-cell malignancies, such as chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). In a phase 1 study, duvelisib showed clinically meaningful activity and acceptable safety in CLL/SLL patients. We report here the results of DUO, a global phase 3 randomized study of duvelisib vs ofatumumab monotherapy for patients with relapsed or refractory (RR) CLL/SLL. Patients were randomized 1:1 to oral duvelisib 25 mg twice daily (n = 160) or ofatumumab IV (n = 159). The study met the primary study end point by significantly improving progression-free survival per independent review committee assessment compared with ofatumumab for all patients (median, 13.3 months vs 9.9 months; hazard ratio [HR] = 0.52; P < .0001), including those with high-risk chromosome 17p13.1 deletions [del(17p)] and/or TP53 mutations (HR = 0.40; P = .0002). The overall response rate was significantly higher with duvelisib (74% vs 45%; P < .0001) regardless of del(17p) status. The most common adverse events were diarrhea, neutropenia, pyrexia, nausea, anemia, and cough on the duvelisib arm, and neutropenia and infusion reactions on the ofatumumab arm. The DUO trial data support duvelisib as a potentially effective treatment option for patients with RR CLL/SLL. This trial was registered at www.clinicaltrials.gov as #NCT02004522.

Phase 1/2 study of eprenetapopt (APR-246) in combination with pembrolizumab in patients with solid tumor malignancies.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS3161-TPS3161
Author(s):  
Ecaterina Elena Dumbrava ◽  
Amit Mahipal ◽  
Xin Gao ◽  
Geoffrey Shapiro ◽  
Jason S. Starr ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Mononuclear Cells ◽  
Phase 1 ◽  
Objective Response ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Tumor Growth Inhibition ◽  
Advanced Solid Tumors ◽  
Peripheral Blood Mononuclear

TPS3161 Background: The p53 pathway has been implicated in antitumor immunity, including antigen presentation and T-cell proliferation. Loss of p53 function can increase resistance to immunotherapy across many tumor types. Eprenetapopt (eprenet) is a small molecule that stabilizes the folded structure of p53, resulting in activation of mutant p53 and stabilization of wild-type (WT) p53. It also targets the cellular redox homeostasis, resulting in induction of apoptosis in tumor cells. In vivo, mice carrying supernumerary copies of the TP53 gene harbor a pro-inflammatory tumor microenvironment, an effect recapitulated in TP53 normal-copy mice treated with eprenetapopt. Combining eprenetapopt and anti-PD1 or anti-CTLA4 therapy resulted in enhanced tumor growth inhibition and improved survival in TP53 WT mice inoculated with B16 melanoma and MC38 colon adenocarcinoma cells . Based on these results, we hypothesized that eprenet-induced p53 stabilization may augment response to immunotherapy. To test this hypothesis, we are conducting a phase 1b/2 study of eprenet in combination with pembrolizumab (eprenet+pembro) in pts with solid tumors. Methods: The primary objectives are to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) and to assess the safety and tolerability of eprenet+pembro in pts with advanced solid tumors. The secondary objectives are to estimate the anti-tumor activity and to describe the pharmacokinetics of the combination. Exploratory objectives include assessing predictive and pharmacodynamic markers of response. The study includes a safety lead-in with a 3+3 dose de-escalation design for pts with advanced solid tumors with known tumor TP53 mutation status ( TP53 WT is acceptable) (max 18 pts), followed by expansion cohorts in pts with NSCLC, gastric/GEJ and urothelial cancer (max 100 pts). In expansion, pts with urothelial and gastric cancers must be naïve to anti-PD-1/ L1 therapy. Eprenet is given IV once daily on Days 1–4 while pembro is administered on Day 3 of each 21-day cycle. The RP2D of eprenet+pembro is considered the dose at which ≤ 1 of 6 pts in a cohort has a dose-limiting toxicity (DLT). Primary endpoints are occurrence of DLTs, adverse events (AEs) and serious AEs with eprenet+pembro. Key secondary endpoints are best objective response, progression free survival and overall survival. Exploratory endpoints include gene mutations by next generation sequencing (including TP53), mRNA expression, multiplex immunohistochemistry and transcriptomics, multiplex flow cytometry on peripheral blood mononuclear cells and cytokines in serum. Continuous monitoring of toxicity will be conducted. The trial opened in May 2020 and is actively enrolling patients. Clinical trial information: NCT04383938.

Safety and efficacy of ofatumumab, a fully human monoclonal anti-CD20 antibody, in patients with relapsed or refractory B-cell chronic lymphocytic leukemia: a phase 1-2 study

Blood ◽  
2008 ◽  
Vol 111 (3) ◽  
pp. 1094-1100 ◽  
Author(s):  
Bertrand Coiffier ◽  
Stéphane Lepretre ◽  
Lars Møller Pedersen ◽  
Ole Gadeberg ◽  
Henrik Fredriksen ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Adverse Events ◽  
Partial Remission ◽  
Phase 1 ◽  
Objective Response ◽  
Median Number ◽  
Maximum Tolerated Dose ◽  
Lymphocytic Leukemia ◽  
Safety And Efficacy ◽  
Anti Cd20

Abstract Safety and efficacy of the fully human anti-CD20 monoclonal antibody, ofatumumab, was analyzed in a multicenter dose-escalating study including 33 patients with relapsed or refractory chronic lymphocytic leukemia. Three cohorts of 3 (A), 3 (B), and 27 (C) patients received 4, once weekly, infusions of ofatumumab at the following doses: (A) one 100 mg and three 500 mg; (B) one 300 mg and three 1000 mg; (C) one 500 mg and three 2000 mg. Sixty-seven percent of the patients were Binet stage B, and the median number of previous treatments was 3. The maximum tolerated dose was not reached. The majority of related adverse events occurred at first infusion, and the number of adverse events decreased at each subsequent infusion. Seventeen (51%) of 33 patients experienced infections, 88% of them of grade 1-2. One event of interstitial pneumonia was fatal; all other cases resolved within one month. The response rate of cohort C was 50% (13/26), one patient having a nodular partial remission and 12 patients partial remission. In conclusion, ofatumumab was found to be well tolerated in patients with chronic lymphocytic leukemia (CLL) in doses up to 2000 mg. Preliminary data on safety and objective response are encouraging and support further studies on the role of ofatumumab in CLL patients. This trial was registered at www.clinicaltrials.gov as no. NCT00093314.

Phase 1/2 study of safety/efficacy using trabectedin, ipilimumab, and nivolumab as first-line treatment of advanced soft tissue sarcoma (STS).

2018 ◽  
Vol 36 (5_suppl) ◽  
pp. TPS46-TPS46 ◽  
Author(s):  
Erlinda Maria Gordon ◽  
Victoria S. Chua-Alcala ◽  
Katherine Kim ◽  
William W. Tseng ◽  
Doris M Quon ◽  
...  
Keyword(s):  
Checkpoint Inhibitors ◽  
Phase 1 ◽  
Objective Response ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Categorical Variables ◽  
Phase 2 ◽  
First Line ◽  
First Line Therapy ◽  
Number Of Patients

TPS46 Background: Sarcoma cells are most immunogenic at the onset of cancer when the immune system can recognize and destroy them. Hence, immune checkpoint inhibitors would be most effective when given as first line therapy. Objectives: (1) To investigate the maximum tolerated dose of trabectedin, an alkylating agent, when given sequentially with ipilimumab, a CTLA4 inhibitor, and nivolumab, a PD-1 inhibitor, in advanced STS, (2) To investigate the objective response rate (ORR), progression free survival (PFS) and overall survival (OS) , and (3) To correlate PFS with PD-L1 and other biomarker expression in patients’ tumors. Methods: Forty patients ≥18 years of age with advanced STS will be enrolled. This is a phase 1/2 study using a defined dose of ipilimumab (1 mg/kg i.v. q 12 weeks), nivolumab (3 mg/kg i.v. q 2 weeks), and escalating doses of trabectedin (1.0, 1.3, 1.5 mg/m2 i.v. q 3 weeks). I. Dose Escalation Phase 1 (previously treated patients): The study will employ the standard “cohort of three” design. The maximum tolerated dose is defined as the highest safely tolerated dose, where not more than one patient experienced DLT, with the next higher dose level having at least two patients who experienced DLT. II. Expansion Phase 2 (previously untreated patients): An additional 22-28 patients will receive trabectedin at the MTD and defined doses of ipilimumab and nivolumab to assess overall safety and potential efficacy in a greater number of patients. Patients may continue treatment until significant disease progression or unacceptable toxicity occurs. Statistical Considerations: NIH CTCAE v4.03 and RECIST v1.1 will be used. Categorical variables will be summarized by the n and percent in each category. Point estimates for efficacy endpoint incidences will be accompanied by a 2-sided 95% exact binomial CI. Time to event endpoints will be summarized descriptively using the KM method. The analyses of all study objectives will be descriptive and hypothesis generating, for planning Phase 2/3 studies. Clinical trial information: NCT 03138161.

ZUMA-8: A phase 1/2 multicenter study evaluating KTE-X19 in patients (pts) with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS7566-TPS7566 ◽  
Author(s):  
Ian Flinn ◽  
Michael Marris ◽  
William G. Wierda ◽  
Steven Coutre ◽  
John M. Pagel ◽  
...  
Keyword(s):  
High Risk ◽  
Multicenter Study ◽  
Residual Disease ◽  
Phase 1 ◽  
Objective Response ◽  
Progression Free Survival ◽  
Lymphocytic Leukemia ◽  
Phase 2 ◽  
T Cell Therapy ◽  
Patient Reported

TPS7566 Background: Despite treatment advances, CLL is largely incurable. First-line targeted therapy with ibrutinib mostly produces durable remissions, but high-risk disease or many prior therapies increases relapse risk (Ghia P, et al. Haematologica. 2014). Relapse after ibrutinib is associated with a poor outcome (Maddocks KJ, et al. JAMA Oncol. 2015). Allogeneic stem cell transplantation potentially offers long-term remissions but has a high risk of morbidity/mortality (Shustik C, et al. Ann Hematol. 2017). Autologous T cells expressing a CD19-specific chimeric antigen receptor (CAR) with a CD28 costimulatory domain may be efficacious against CLL (Kochenderfer JN, et al. Blood. 2012). KTE-X19 is an autologous anti-CD19 CAR T cell therapy under investigation for R/R hematologic malignancies and may offer longer durable remissions with manageable safety in pts with R/R CLL. ZUMA-8 is a Phase 1/2 multicenter study for pts with R/R CLL. Methods: Adult pts must have R/R CLL with ≥ 2 prior treatment regimens, disease progression on ibrutinib, ECOG 0-1, and adequate organ function. Phase 1 will enroll 12-18 pts to assess dose-limiting toxicities (DLTs) with a 6 + 3 dose escalation/de-escalation design; 30 more pts may be enrolled to further assess safety. Phase 2 will enroll ≈60 pts to evaluate efficacy and safety. Pts will undergo leukapheresis followed by optional bridging therapy. Cyclophosphamide (500 mg/m2) and fludarabine (30 mg/m2) conditioning chemotherapy will be given on Days -5, -4 and -3. KTE-X19 will be given on Day 0 at 0.5, 1 or 2 × 106 KTE-X19 cells/kg. The primary endpoint is incidence of DLTs for Phase 1 and independent review committee-assessed objective response rate (ORR) per iwCLL 2018 criteria for Phase 2. Secondary endpoints include complete remission (CR) rate, investigator-assessed ORR, minimal residual disease (MRD) negativity rate, MRD-negative CR rate, duration of response, progression-free survival, overall survival, safety, and patient-reported outcomes (Phase 2). Serum cytokine and blood KTE-X19 cell levels over time and level of anti-KTE-X19 antibodies are exploratory endpoints. Accrual is ongoing. Clinical trial information: NCT03624036.

Updated results from a phase Ib trial of regorafenib plus nivolumab in patients with advanced colorectal or gastric cancer (REGONIVO, EPOC1603).

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 135-135
Author(s):  
Kohei Shitara ◽  
Hiroki Hara ◽  
Naoki Takahashi ◽  
Takashi Kojima ◽  
Akihito Kawazoe ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Phase 1 ◽  
Randomized Study ◽  
Objective Response ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Dose Finding ◽  
Significant Difference ◽  
One Year ◽  
Anti Tumor Activity

135 Background: In the phase 1 REGONIVO study, regorafenib of 80 mg/day plus nivolumab showed manageable safety profiles and encouraging anti-tumor activity for advanced colorectal cancer (CRC) or gastric cancer (GC) with objective response rate (ORR) of 36% in CRC and 44% in GC (Fukuoka, et al. ASCO 2019). Updated efficacy results are presented. Methods: Enrolled patients (pts) received regorafenib plus nivolumab in a dose-finding phase to estimate the maximum tolerated dose (MTD). Additional pts were enrolled in a dose-expansion phase. Regorafenib of 80 to 160 mg was administered once daily for 21 on 7 days off with nivolumab 3 mg/kg every 2 weeks. The primary endpoint was dose-limiting toxicity (DLT) during cycle one to estimate the MTD and the recommended dose. PD-L1 combined positive score (CPS) was assessed using the anti–PD-L1 28-8 antibody. Tumor mutation burden (TMB) was measured using Oncomine tumor mutation load assay. Results: Fifty pts were enrolled (25 CRC; 25 GC) until October 2018 with median prior treatment line of 3. Efficacy results were updated as of September 1st 2019. One CRC pt was with MSI-high but all other pts were with MSS or MMR-proficient. Among the 20 pts (9 CRC and 11 GC) with objective response (40%), responses are still ongoing in 13 pts (7 CRC and 6 GC) and the median duration of response was not reached (NR). Median progression free survival (PFS) was 7.8 months in CRC (95% CI, 2.8- NR) and 5.5 months (95% CI, 2.6-10.2 months) in GC. One-year PFS rate was 41.7% in CRC and 22.4% in GC. Median overall survival (OS) was not reached in CRC (95% CI, 9.7-NR) and 12.1 months (95% CI, 5.2-NR) in GC. One-year OS rate was 68% in CRC and 55.3% in GC. No significant difference of PFS and ORR was observed in CRC according to PD-L1 and TMB. Conclusions: Encouraging anti-tumor activity of the combination of regorafenib plus nivolumab had been maintained with long-term follow-up. A randomized study for MSS CRC is under planning. Clinical trial information: NCT03406871.

A phase Ib study of alofanib, an allosteric FGFR2 inhibitor, in patients with advanced or metastatic gastric cancer.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. TPS466-TPS466
Author(s):  
Galina Statsenko ◽  
Mikhail Fedyanin ◽  
Vladimir Moiseyenko ◽  
Liubov Yu Vladimirova ◽  
Ilya Tsimafeyeu ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Standard Dose ◽  
Objective Response ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Metastatic Gastric Cancer ◽  
Maximum Tolerated Dose ◽  
Inhibitory Effect ◽  
Pharmacokinetic Parameters ◽  
And Function

TPS466 Background: Fibroblast growth factor receptor 2 (FGFR2) is amplified or overexpressed in 3% to 61% of patients with gastric cancer and associated with a poor prognosis. Acquired mutations in FGFR2 develop resistance to multikinase inhibitors. Besides, resistance to monoclonal antibodies depends on the type of FGFR2 isoforms IIIc or IIIb expressed by cancer cells. Alofanib (RPT835) is a novel selective allosteric inhibitor of FGFR2. Alofanib could bind to the non-active site of FGFR2 extracellular domain and had an inhibitory effect on FGF2-induced phosphorylation of FRS2α. On preclinical models no severe organ and function test changes were observed. Based on these results, alofanib has advanced into clinical evaluation. Methods: RPT835GC1B is a Phase 1b study, being conducted in at least four sites in Russia, evaluating the safety and preliminary efficacy of alofanib in patients with advanced and metastatic gastric adenocarcinoma pretreated with ≥ 1 previous lines of therapy. This trial consists of two parts. The standard dose-escalation part (design 3+3) aims to establish the maximum tolerated dose (MTD) or recommended phase 2 dose (R2PD) as a primary endpoint. The first part of the study includes a 28-day period when alofanib is administered daily intravenously for 5-days followed by a 2-day interval (rest). There are five dose levels: 50, 100, 165, 250, and 350 mg/m2. The dose-expansion phase accrues additional 20 patients, where comprehensive information to be collected. Secondary endpoints include pharmacokinetic parameters, rate of adverse events, progression-free survival, overall survival, and objective response rate. All patients will receive alofanib until disease progression or unacceptable toxicity. FGFR2 amplification, fusion, and overexpression will be assessed as well. Clinical trial information: NCT04071184.

scholarly journals Inhibition of Syk with fostamatinib disodium has significant clinical activity in non-Hodgkin lymphoma and chronic lymphocytic leukemia

Blood ◽  
2010 ◽  
Vol 115 (13) ◽  
pp. 2578-2585 ◽  
Author(s):  
Jonathan W. Friedberg ◽  
Jeff Sharman ◽  
John Sweetenham ◽  
Patrick B. Johnston ◽  
Julie M. Vose ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Hodgkin Lymphoma ◽  
Cell Lymphoma ◽  
Phase 1 ◽  
Objective Response ◽  
B Cell Lymphoma ◽  
Lymphocytic Leukemia ◽  
Primary Tumors ◽  
Non Hodgkin Lymphoma

AbstractCertain malignant B cells rely on B-cell receptor (BCR)–mediated survival signals. Spleen tyrosine kinase (Syk) initiates and amplifies the BCR signal. In in vivo analyses of B-cell lymphoma cell lines and primary tumors, Syk inhibition induces apoptosis. These data prompted a phase 1/2 clinical trial of fostamatinib disodium, the first clinically available oral Syk inhibitor, in patients with recurrent B-cell non-Hodgkin lymphoma (B-NHL). Dose-limiting toxicity in the phase 1 portion was neutropenia, diarrhea, and thrombocytopenia, and 200 mg twice daily was chosen for phase 2 testing. Sixty-eight patients with recurrent B-NHL were then enrolled in 3 cohorts: (1) diffuse large B-cell lymphoma (DLBCL), (2) follicular lymphoma (FL), and (3) other NHL, including mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), mucosa-associated lymphoid tissue lymphoma, lymphoplasmacytic lymphomas, and small lymphocytic leukemia/chronic lymphocytic leukemia (SLL/CLL). Common toxicities included diarrhea, fatigue, cytopenias, hypertension, and nausea. Objective response rates were 22% (5 of 23) for DLBCL, 10% (2 of 21) for FL, 55% (6 of 11) for SLL/CLL, and 11% (1/9) for MCL. Median progression-free survival was 4.2 months. Disrupting BCR-induced signaling by inhibiting Syk represents a novel and active therapeutic approach for NHL and SLL/CLL. This trial was registered at www.clinicaltrials.gov as #NCT00446095.

Recombinant Interleukin-21 Plus Rituximab: Clinical Activity in a Phase 1, Dose-Finding Trial in Relapsed Low-Grade B Cell Lymphoma.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2577-2577 ◽  
Author(s):  
John M. Timmerman ◽  
John C. Byrd ◽  
David J. Andorsky ◽  
Muriel F. Siadak ◽  
Todd DeVries ◽  
...  
Keyword(s):  
T Cells ◽  
Follicular Lymphoma ◽  
B Cell ◽  
Disease Progression ◽  
Dose Escalation ◽  
Combination Treatment ◽  
Phase 1 ◽  
Lymphocytic Leukemia ◽  
Interleukin 21 ◽  
Expansion Cohort

Abstract Interleukin-21 (IL-21) is a member of the common gamma chain cytokine family, which includes IL-2, IL-7 and IL-15, and serves to activate NK cells and CD8+ T cells, as well as modulate B cell functions. Like IL-2, IL-21 can enhance antibody-dependent cellular cytotoxicity (ADCC) against tumor cells. However, unlike IL-2, IL-21 can render effector T cells resistant to suppression by T reg cells, and can have direct anti-tumor effects against malignant B cells. IL-21 has been shown to promote apoptosis in follicular lymphoma cells, and to induce granzyme B expression in chronic lymphocytic leukemia cells and sensitize them to apoptosis. In a human lymphoma xenograft model, combination treatment with rituximab plus recombinant IL-21 (rIL-21) led to increased survival compared to either agent alone. To further evaluate the potential safety, pharmacokinetics, and anti-tumor effects of combining rIL-21 with rituximab, a phase 1, two-part dose-escalation study was initiated in patients with relapsed CD20+ B cell lymphomas. For dose escalation, cohorts of 3 patients each received weekly rituximab (375 mg/m2) on days -7, 0, 7, 14, and 21, and rIL-21 at 1 of 3 dose levels (30, 100, or 150 g/kg) on days 0, 7, 14, and 21. Patients without disease progression at day 36 were eligible to receive a second cycle beginning 2 weeks later, and CT scan assessments were repeated at day 50 of cycle 2. Enrollment to an expansion cohort of up to 12 additional patients for treatment at the maximum tolerated dose was initiated. A total of 15 patients have been enrolled to date, including 9 dose-escalation patients, all of whom are evaluable for clinical response. The latter include 4 with follicular lymphoma, 4 with small lymphocytic leukemia (SLL), and 1 with marginal zone lymphoma. The median number of prior regimens was 3 (range 1–8), with 8/9 patients having had prior rituximab (1–3 cycles). No patient receiving 100 g/kg or higher of rIL-21 had disease progression, and 7 of 9 patients completed 2 treatment cycles. Overall best responses included 2 CR, 3 PR (including 2 patients whose last response to rituximab lasted < 6 months), and 3 SD by Cheson criteria, for an overall response rate of 56%. No dose limiting toxicities occurred in the first cycle at any dose. Most adverse events were grade 1–2 and included flu-like symptoms, fatigue, pruritus, insomnia, and diarrhea. Laboratory abnormalities were generally mild to moderate and included lymphopenia, transaminase elevations, thrombocytopenia in one patient and hypophosphatemia. Retreatment at 150 g/kg was associated with transient grade 3 nausea, vomiting, and diarrhea in one patient, while a second patient had grade 2 lower extremity edema. Thus, the 100 g/kg dose was chosen for cohort expansion. Combination treatment with interleukin-21 plus rituximab for up to two 4-week cycles is generally well-tolerated and associated with clinical responses, even in subjects heavily pre-treated with rituximab. Enrollment in the 100 g/kg expansion cohort is ongoing. These encouraging results support further evaluation of this combination in phase 2 trials.

Interim analysis results of surufatinib in U.S. patients with neuroendocrine tumors (NETs).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4114-4114
Author(s):  
Andrew Scott Paulson ◽  
Daneng Li ◽  
Max W. Sung ◽  
Christopher Tucci ◽  
John S. Kauh ◽  
...  
Keyword(s):  
Safety Profile ◽  
Tyrosine Kinases ◽  
Phase 1 ◽  
Objective Response ◽  
Progression Free Survival ◽  
Median Number ◽  
Maximum Tolerated Dose ◽  
Phase 3 ◽  
Heavily Pretreated ◽  
Grade 3

4114 Background: Surufatinib (S) is a targeted inhibitor of tyrosine kinases VEGFR1, 2, and 3; FGFR1; and CSF-1R. A manageable safety profile and statistically significant efficacy of S have previously been demonstrated in patients (pts) with advanced NETs of extrapancreatic (epNET) and pancreatic (pNET) origin in 2 phase 3 randomized trials conducted in China (SANET-ep, NCT02588170; SANET-p, NCT02589821). Pts with epNETs achieved a median progression free survival (PFS) of 9.2 v 3.8 months (mo) (hazard ratio [HR] 0.334; p < 0.0001), and pts with pNETs achieved a median PFS of 10.9 v 3.7 mo (HR 0.491; p = 0.0011), with S v placebo, respectively. S has recently been approved for the treatment (tx) of pts with epNETs in China. Methods: A phase 1, dose escalation (ESC)/expansion (EXP) trial was conducted to evaluate and confirm the efficacy and safety of S in US pts. ESC was completed, and the maximum tolerated dose and recommend phase 2 dose were determined to be 300 mg, same as previous trials. The EXP completed enrollment of the epNET and pNET cohorts, and the primary endpoint was investigator-assessed PFS rate at 11 mo. Secondary objectives included assessment of safety and PK. Results: 32 pts with heavily pretreated progressive NETs (16 epNET and pNET each) were enrolled in the dose EXP. The median age was 62.2 years (44-75) and 64.4 years (39-72) for epNET and pNET pts, respectively. 65.6% of pts received ≥3 prior lines of tx (median lines of therapy: epNET: 2 [2-5]; pNET: 4 [1-8]), and all pts previously received everolimus and/or sunitinib. As of the data cutoff of 30-Jun-20, 7 pts remained on tx (4 epNET; 3 pNET). The median number of tx cycles was 8.0 (2, 15) for epNET and 8.5 (2, 23) for pNET pts. The PFS rate at 11 mo was 51.1% (95% confidence interval [CI]: 12.8, 80.3) for pts with epNETs and 57.4% (95% CI: 28.7, 78.2) for pts with pNETs. The observed mPFS was 11.50 mo (95% CI: 6.47, 11.50) and 15.18 mo (95% CI: 5.19, NR) for pts with epNETs and pNETs, respectively. An objective response rate (ORR) of 6.3% was observed for pts with epNETs and 18.8% for pts with pNETs. A disease control rate of 90.6% (95% CI: 75.0, 98.0) was observed for all NET pts (93.8% epNET; 87.5% pNET). The safety profile of S remains consistent with previously completed trials. All pts (n = 32) had reported at least 1 adverse event (AE), and 24 pts (75%) reported AEs ≥grade 3. The most common AEs of any grade reported were fatigue (46.9%), hypertension (43.8%), proteinuria (37.5%), diarrhea (34.4%), vomiting (28.1%), and nausea (25.0%). The most commonly reported AEs ≥grade 3 ( > 5%) were hypertension (37.5%); diarrhea (9.4%); and proteinuria, dysphagia, and anemia (6.3% each). AEs leading to tx discontinuation occurred in 21.9% of pts. Conclusions: S has demonstrated antitumor activity in heavily pretreated US pts with progressive NETs with a manageable safety profile that is consistent with 2 completed phase 3 studies. S continues to be studied in other ongoing clinical trials globally. Clinical trial information: NCT02549937.

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