Phase 2 study of PVAG (prednisone, vinblastine, doxorubicin, gemcitabine) in elderly patients with early unfavorable or advanced stage Hodgkin lymphoma

Blood ◽  
2011 ◽  
Vol 118 (24) ◽  
pp. 6292-6298 ◽  
Author(s):  
Boris Böll ◽  
Henning Bredenfeld ◽  
Helen Görgen ◽  
Teresa Halbsguth ◽  
Hans T. Eich ◽  
...  
Keyword(s):  
Hodgkin Lymphoma ◽  
Dose Intensity ◽  
Progression Free Survival ◽  
Observation Time ◽  
Advanced Stage ◽  
Phase 2 ◽  
Who Grade ◽  
Stage Disease ◽  
Phase 2 Study ◽  
Grade 3

Abstract Approximately 20% of all Hodgkin lymphoma (HL) patients are older than 60 years and have a poor prognosis, mainly because of increased treatment-related toxicity resulting in reduced overall dose intensity and more treatment-related mortality. To possibly improve the treatment of elderly HL patients, the German Hodgkin Study Group developed a new regimen, PVAG (prednisone, vinblastine, doxorubicin, and gemcitabine). In this multicenter phase 2 study, elderly HL patients in early unfavorable and advanced stages received 6 to 8 cycles of PVAG and additional radiotherapy if they were not in complete remission (CR) after chemotherapy. Endpoints included feasibility, acute toxicity, and response rate. Fifty-nine patients 60 to 75 years of age (median, 68 years) were eligible for analysis; 93% had advanced stage disease. WHO grade 3/4 toxicities were documented in 43 patients; 46 patients responded with CR/CR uncertain (78%). Within 37 months median observation time, 15 progressions or relapses and 17 deaths were observed, of which 8 were related to HL and 1 was the result of treatment-related toxicity. The 3-year estimates for overall survival and progression-free survival were 66% (95% CI, 50%-78%) and 58% (95% CI, 43%-71%), respectively. We conclude that PVAG is safe and feasible in elderly HL patients. This trial was registered at www.clinicaltrials.gov as #NCT00147875.

Treatment Outcomes and Relative Dose Intensity of Chemotherapy in Slovene Patients With Advanced Hodgkin Lymphoma

2022 ◽  
Author(s):  
Samo Rozman ◽  
Nina Ružić Gorenjec ◽  
Barbara Jezeršek Novaković
Keyword(s):  
Hodgkin Lymphoma ◽  
Proportional Hazards ◽  
Stage Iv ◽  
Dose Intensity ◽  
Progression Free Survival ◽  
Cox Proportional Hazards ◽  
Relative Dose Intensity ◽  
Cox Proportional Hazards Models ◽  
Stage Disease ◽  
Stage Iv Disease

Abstract This retrospective study was undertaken to investigate the association of relative dose intensity (RDI) with the outcome of Hodgkin lymphoma (HL) patients with advanced stage disease receiving ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) and escalated BEACOPP regimen (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone). A total of 114 HL patients treated between 2004 and 2013 were enrolled for evaluation. RDI calculations were based on a Hryniuk's model. The association of variables with overall survival (OS) and progression-free survival (PFS) was analysed using univariate and multivariate Cox proportional hazards models. The median age of patients was 39 years, majority of patients were males and had stage IV disease. Fifty-four patients received ABVD and 60 received BEACOPP chemotherapy with 24 and 4 deaths, respectively. Patients in BEACOPP group were significantly younger with lower Charlson comorbidity index (CCI) in comparison with ABVD group, making the comparison of groups impossible. In ABVD group, RDI was not significantly associated with OS (p=0.590) or PFS (p=0.354) in a multivariate model where age was controlled. The low number of events prevented the analysis in the BEACOPP group. Patients' age was strongly associated with both OS and PFS: all statistically significant predictors for OS and PFS from univariate analyses (chemotherapy regimen, CCI, RDI) lost its effect in multivariate analyses where age was controlled. Based on our observations, we can conclude that RDI is not associated with the OS or PFS after the age is controlled, neither in all patients combined nor in individual chemotherapy groups.

scholarly journals Phase 2 study using oral thalidomide-cyclophosphamide-prednisone for idiopathic multicentric Castleman disease

Blood ◽  
2019 ◽  
Vol 133 (16) ◽  
pp. 1720-1728 ◽  
Author(s):  
Lu Zhang ◽  
Ai-lin Zhao ◽  
Ming-hui Duan ◽  
Zhi-yuan Li ◽  
Xin-xin Cao ◽  
...  
Keyword(s):  
Treatment Failure ◽  
Progression Free Survival ◽  
Castleman Disease ◽  
Phase 2 ◽  
Newly Diagnosed ◽  
Free Survival ◽  
Multicentric Castleman Disease ◽  
End Point ◽  
Phase 2 Study ◽  
Grade 3

Abstract Idiopathic multicentric Castleman disease (iMCD) is a rare lymphoproliferative disorder. The anti–interleukin 6 (IL-6) therapy siltuximab is not available everywhere, and is not effective for over one-half of patients. Alternative treatment approaches are urgently needed. In the first iMCD clinical trial directed against a target other than IL-6 signaling, we investigated a thalidomide-cyclophosphamide-prednisone (TCP) regimen in newly diagnosed iMCD patients. This single-center, single-arm, phase 2 study enrolled 25 newly diagnosed iMCD patients between June 2015 and June 2018. The TCP regimen (thalidomide 100 mg daily for 2 years; oral cyclophosphamide 300 mg/m2 weekly for 1 year; prednisone 1 mg/kg twice a week for 1 year) was administered for 2 years or until treatment failure. The primary end point was durable tumor and symptomatic response for at least 24 weeks. Twelve patients (48%) achieved the primary end point with no relapse, 3 patients (12%) demonstrated stable disease, and 10 patients (40%) were evaluated as treatment failure. Even when considering all patients, there were significant (P < .05) improvements in median symptom score, IL-6 level, hemoglobin, erythrocyte sedimentation rate, albumin, and immunoglobulin G. Among responders, the median levels of all evaluated parameters significantly improved, to the normal range, after treatment. The regimen was well tolerated. One patient died of pulmonary infection and 1 patient had a grade 3 adverse event (rash); 2 patients died following disease progression. Estimated 1-year progression-free survival and overall survival were 60% and 88%, respectively. The TCP regimen is an effective and safe treatment of newly diagnosed iMCD patients, particularly when siltuximab is unavailable. This trial was registered at www.clinicaltrials.gov as #NCT03043105.

scholarly journals Phase 2 study of rituximab plus ABVD in patients with newly diagnosed classical Hodgkin lymphoma

Blood ◽  
2012 ◽  
Vol 119 (18) ◽  
pp. 4123-4128 ◽  
Author(s):  
Anas Younes ◽  
Yasuhiro Oki ◽  
Peter McLaughlin ◽  
Amanda R. Copeland ◽  
Andre Goy ◽  
...  
Keyword(s):  
Hodgkin Lymphoma ◽  
Prognostic Score ◽  
Survival Rates ◽  
Clinical Activity ◽  
Advanced Stage ◽  
Phase 2 ◽  
Classical Hodgkin Lymphoma ◽  
Phase 2 Study ◽  
Standard Doxorubicin ◽  
Intent To Treat

Abstract In the present study, we evaluated the efficacy and safety of rituximab in combination with standard doxorubicin, bleomycin, vinblastine, and dacarbazine (RABVD) in patients with classical Hodgkin lymphoma (cHL). In this phase 2 study, patients with chemotherapy-naive, advanced-stage cHL were treated with rituximab 375 mg/m2 weekly for 6 weeks and standard ABVD for 6 cycles. The primary outcome was event-free survival (EFS) at 5 years. Eighty-five patients were enrolled, of whom 78 were eligible. With a median follow-up duration of 68 months (range, 26-110), and based on an intent-to-treat analysis, the 5-year EFS and overall survival rates were 83% and 96%, respectively. The 5-year EFS for patients with stage III/IV cHLwas 82%. Furthermore, the 5-year EFS for patients with an International Prognostic Score of 0-2 was 88% and for those with a score of > 2, it was 73%. The most frequent treatment-related grade 3 or 4 adverse events were neutropenia (23%), fatigue (9%), and nausea (8%). Our results demonstrate that the addition of rituximab to ABVD is safe and has a promising clinical activity in patients with advanced-stage cHL. These data are currently being confirmed in a multicenter randomized trial. This trial has been completed and is registered with www.clinicaltrials.gov as NCT00504504.

A phase 2 trial of lenvatinib 18 mg versus 14 mg once daily (QD) in combination with everolimus (5 mg QD) in renal cell carcinoma (RCC) after 1 prior VEGF-targeted treatment.

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. TPS707-TPS707
Author(s):  
Hilary Glen ◽  
Javier Puente ◽  
Daniel Yick Chin Heng ◽  
Sun Young Rha ◽  
Di Li ◽  
...  
Keyword(s):  
Objective Response ◽  
Progression Free Survival ◽  
Final Analysis ◽  
The United States ◽  
Similar Efficacy ◽  
P Value ◽  
Phase 2 ◽  
Double Blind ◽  
Phase 2 Study ◽  
Grade 3

TPS707 Background: Based on findings from a randomized phase 2 study (Study 205), lenvatinib (LEN) + everolimus (EVE) was approved in the United States and European Union for patients (pts) with advanced RCC following 1 prior anti-angiogenic therapy. In that study, LEN 18 mg QD + EVE 5 mg QD significantly prolonged progression-free survival (PFS) compared with either monotherapy. In the LEN+EVE cohort, grades 3 and 4 treatment-emergent adverse events (TEAEs) occurred in 71% of pts. We report the design of an ongoing, multicenter, randomized, double-blind, phase 2 study (Study 218) to evaluate if a lower LEN starting dosage regimen provides similar efficacy with a better safety profile than LEN 18 mg + EVE 5 mg (NCT03173560). Methods: Eligible pts are aged ≥ 18 years with advanced clear cell RCC, 1 prior anti-VEGF therapy, ≥ 1 measurable target lesion per RECIST 1.1, a KPS score of ≥ 70, and prior nivolumab is allowed. Pts will receive LEN 18 mg or 14 mg QD + EVE 5 mg QD in 28-day cycles until disease progression, unacceptable toxicity, or withdrawal of consent. The LEN 14-mg dose will be escalated to 18 mg if no intolerable grade 2, or any grade ≥ 3 TEAEs requiring dose reduction occur in cycle 1. The primary endpoints are objective response rate (ORR) at week 24 (ORR24W) and the proportion of pts with intolerable grade 2 and any grade ≥ 3 TEAEs within 24 wks after randomization. Secondary endpoints include PFS and ORR. An estimated 306 pts will be randomized. Sample size is based on detecting noninferiority (NI) of ORR24W and superiority of the primary safety endpoint. Two interim analyses (IA) will be performed when 150 and 200 pts have completed 24 wks of follow-up or discontinue earlier. Each analysis will test NI and futility of the LEN 14-mg arm ORR24W vs the 18-mg arm ORR24W. An O’Brien-Fleming boundary will be used for NI. If the 1-sided P-value is ≤ 0.005 at the first IA, ≤ 0.014 at the second IA, or ≤ 0.045 at the final analysis, then NI in ORR24W will be claimed. If the futility boundary is crossed (ie, 1-sided P-value is ≥ 0.776 at the first IA or ≥ 0.207 at the second IA), then futility will be claimed. Clinical trial information: NCT03173560.

scholarly journals Phase 2 study of rituximab-ABVD in classical Hodgkin lymphoma

Blood ◽  
2012 ◽  
Vol 119 (18) ◽  
pp. 4129-4132 ◽  
Author(s):  
Yvette L. Kasamon ◽  
Heather A. Jacene ◽  
Christopher D. Gocke ◽  
Lode J. Swinnen ◽  
Douglas E. Gladstone ◽  
...  
Keyword(s):  
B Cells ◽  
Hodgkin Lymphoma ◽  
Copy Number ◽  
Survival Rates ◽  
Dose Intensity ◽  
Phase 2 ◽  
Classical Hodgkin Lymphoma ◽  
Multicenter Phase ◽  
Phase 2 Study ◽  
Overall Survival Rates

Abstract In classical Hodgkin lymphoma, circulating clonotypic malignant cells express CD20, which potentially explains the observed activity of rituximab. This multicenter phase 2 study investigated the combination of rituximab-ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) for stage II-IV untreated classical Hodgkin lymphoma. A goal was to assess the behavior of circulating clonotypic B cells clinically. Of 49 evaluable patients, 69% had stage IIB-IV disease; 8% had CD20+ Hodgkin and Reed-Sternberg cells. Rituximab-ABVD was generally well tolerated. Delivered relative dose intensity was 94% for AVD and 79% for bleomycin. After 6 cycles, 81% of patients were in complete remission. Only 8% received radiation therapy. The actuarial 3-year event-free and overall survival rates were 83% and 98%, respectively. EBV copy number in plasma fell dramatically during cycle 1 in patients with EBV+ tumors. Persistence of detectable circulating clonotypic B cells was associated with a greater relapse frequency (P < .05). Rituximab-ABVD and clonotypic B cells warrant additional study in classical Hodgkin lymphoma. This trial was registered at www.clinicaltrials.gov as NCT00369681.

Tislelizumab (BGB-A317) for relapsed/refractory (R/R) classical Hodgkin lymphoma (cHL): Long-term follow-up efficacy and safety results from a phase 2 study.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e19507-e19507
Author(s):  
Yuqin Song ◽  
Quanli Gao ◽  
Huilai Zhang ◽  
Lei Fan ◽  
Jianfeng Zhou ◽  
...  
Keyword(s):  
Progression Free Survival ◽  
Cell Transplant ◽  
Upper Respiratory Tract ◽  
Phase 2 ◽  
Phase 2 Study ◽  
Long Term Treatment ◽  
Long Term Follow Up ◽  
Grade 3

e19507 Background: Tislelizumab is a humanized IgG4 monoclonal antibody with high affinity/specificity for programmed cell death protein 1 (PD-1). It was engineered to minimize binding to Fc-γ receptors on macrophages, thereby decreasing antibody-dependent phagocytosis, a potential mechanism of T-cell clearance and resistance to anti–PD-1 therapy. Tislelizumab therapy was highly active in autologous stem cell transplant (ASCT)-failed or ineligible patients with R/R cHL ( Leukemia. 2020;34:533). Here we report results from up to 3 years follow-up. Methods: This asingle-arm, multicenter phase 2 study (NCT03209973) of 200 mg tislelizumab administered intravenously to patients (pts) with R/R cHL every 3 weeks until progressive disease (PD) or unacceptable toxicity. Patients were eligible if they: failed to achieve a response or progressed after ASCT, or: received ≥2 lines of prior systemic chemotherapy for cHL and were ineligible for ASCT. Primary endpoint was overall response rate (ORR) assessed by an independent review committee (IRC) per Lugano criteria ( J Clin Oncol. 2014;32:3059). Secondary endpoints were progression-free survival (PFS), duration of response (DOR), complete response (CR) rate, and time to response (TTR) per IRC, safety, and tolerability. Results: Pts (N=70) from 11 centers in China were enrolled and treated; characteristics have been previously reported. As of the data cutoff date (Nov 2, 2020), median follow-up was 33.8 months (range, 3.4-38.6). Pts still on treatment at the end of study (n=33; 47.1%) entered a long-term extension study. Efficacy data is presented in the Table below. In the 13 pts who received prior ASCT, 11 (84.6%) achieved CR. The most common treatment-emergent adverse events (AEs; ≥30%) were pyrexia (57.1%), upper respiratory tract infection (38.6%), hypothyroidism (37.1%), and increased weight (34.3%). Treatment-related grade ≥3 AEs (≥2 pts) were pneumonitis, hypertension, neutropenia, lipase increased, weight increased, and increased creatine phosphokinase (CPK; 2.9% each). Immune-related AEs were reported in 32 pts (45.7%), with grade ≥3 AEs in 8 pts (11.4%): pneumonitis (4) and skin adverse reactions, nephritis, lipase increased, and blood CPK increased (1 each). AEs led to treatment discontinuation in 6 pts (8.6%). Conclusions: Long-term follow-up of R/R cHL pts treated with tislelizumab further demonstrated the substantial therapeutic activity and continued PFS benefit. There were no new safety concerns identified for long-term treatment with tislelizumab. Clinical trial information: NCT03209973. [Table: see text]

Tislelizumab in combination with chemotherapy for the treatment of Chinese patients (pts) with esophageal squamous cell carcinoma (ESCC): Results from one cohort of an ongoing phase 2 study.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 14-14 ◽  
Author(s):  
Nong Xu ◽  
Xianglin Yuan ◽  
Buhai Wang ◽  
Yu-Xian Bai ◽  
En Xiao Li ◽  
...  
Keyword(s):  
Locally Advanced ◽  
Dose Intensity ◽  
Chinese Patients ◽  
Combination Regimen ◽  
Phase 2 ◽  
Activity Data ◽  
First Line Therapy ◽  
Cell Clearance ◽  
Phase 2 Study ◽  
Grade 3

14 Background: Tislelizumab, a humanized IgG4 mAb with high affinity and specificity for PD-1, is specifically engineered to minimize binding to FcγR on macrophages, thereby abrogating antibody-dependent phagocytosis, a potential mechanism of T-cell clearance and resistance to anti-PD-1 therapy. This phase 2 study assessed the safety and tolerability of tislelizumab combined with chemotherapy as first-line therapy in pts with gastric cancer and ESCC; the results of the ESCC cohort are presented here. Methods: Chinese pts with inoperable, locally advanced ESCC were treated with tislelizumab (200 mg IV Q3W), cisplatin (80 mg/m² IV Q3W for up to six cycles), and fluorouracil (800 mg/m²/d, days 1-5 IV Q3W for up to six cycles). Safety/tolerability of the combination regimen was assessed by monitoring adverse events (AEs) per NCI-CTCAE v4.03 criteria. Results: As of 13 June 2018, 15 pts (median age, 61 yrs; male/female, 14/1) were enrolled. The median treatment duration was 108 days (range 21-201). The mean (Q1, Q3) dose intensity was 0.92 (0.91, 0.97) for tislelizumab, 0.91 (0.90, 0.98) for cisplatin, and 0.78 (0.72, 0.97) for 5-FU. Among 15 pts, AEs occurring in > 2 pts reported to be related to chemotherapy and/or tislelizumab are detailed in the table. One pt experienced grade 5 hepatic dysfunction (possibly from progressive disease and underlying hepatitis) which was possibly related to study treatment, according to the investigator. Four pts discontinued study treatment due to AEs (grade 3 tracheal fistula, grade 3 lung infection, grade 2 pneumonitis, and grade 3 increase in aspartate aminotransferase). The antitumor activity data remain unmatured and may be updated later. Conclusions: Tislelizumab combined with chemotherapy was generally well tolerated in pts with advanced ESCC. Clinical trial information: NCT03469557. [Table: see text]

scholarly journals ATIM-45. LONG TERM FOLLOW-UP OF A PHASE I/II STUDY TESTING THE TOXICITIES AND EFFICACY OF PEMBROLIZUMAB IN COMBINATION WITH MRI-GUIDED LASER INTERSTITIAL THERMAL THERAPY (LITT) IN RECURRENT MALIGNANT GLIOMAS

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi11-vi11
Author(s):  
Jian Campian ◽  
Ashley Ghiaseddin ◽  
Maryam Rahman ◽  
Jiayi Huang ◽  
George Ansstas ◽  
...  
Keyword(s):  
Primary Endpoint ◽  
Anaplastic Astrocytoma ◽  
Phase 1 ◽  
Malignant Gliomas ◽  
Progression Free Survival ◽  
High Grade Glioma ◽  
Phase 2 ◽  
Who Grade ◽  
Grade 3 ◽  
Recurrent Gbm

Abstract BACKGROUND LITT was recently demonstrated to induce temporary blood-brain barrier disruption, possibly allowing bilateral trafficking of tumor neoantigens and immune cells to induce glioma-specific immune activation - a phenomenon akin to in situ tumor vaccination. We hypothesize that combining LITT with immune checkpoint inhibition will create a synergistic therapy for recurrent GBM. METHODS The phase 1 study is a standard 3x3 design with a maximum of 18 patients with bevacizumab-naïve recurrent WHO grade 3–4 glioma. The primary endpoint is safety and toxicity of LITT plus pembrolizumab at 100, 150, or 200mg IV q3weeks. Phase 2 includes 40 patients with bevacizumab-naïve recurrent GBM, equally randomized to either pembrolizumab alone or LITT plus pembrolizumab, with progression-free survival as the primary endpoint. Serial immunophenotyping will be performed to evaluate potential positive synergy between LITT and pembrolizumab. RESULTS Phase 1 accrual was completed with 9 patients (3 at each pembrolizumab dose level). Two had recurrent anaplastic astrocytoma and 7 recurrent GBM. There was no dose-limiting toxicity with pembrolizumab 200mg IV q3weeks. The median number of doses given per patient was 9 (range 2 to 47). Severe adverse events possibly related to the study treatment included a grade 3 rash and diarrhea in 1 patient (11%) and grade 3 pneumonitis and hypotension in another patient (11%). No grade 3/4 intracranial edema deemed related to study treatment was observed. To date, four (44%) of these patients are still alive without tumor progression. Two (22%) GBM patients have not progressed for 29 and 33 months, respectively. Two (22%) anaplastic astrocytoma patient have not progressed for 23 and 24 months, respectively. CONCLUSIONS LITT plus pemprolizumab 200mg IV q3weeks is well tolerated in patients with recurrent high-grade glioma. Prolonged stable diseases were observed in almost half of patients treated. Phase 2 study is ongoing and will be updated.

scholarly journals CTNI-45. A PHASE 1B/2 CLINICAL STUDY OF NAPABUCASIN IN COMBINATION WITH TEMOZOLOMIDE FOR ADULT PATIENTS WITH RECURRENT OR PROGRESSED GLIOBLASTOMA MULTIFORME (GBM)

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii52-ii52
Author(s):  
Andrew Chi ◽  
Paula DeRobles ◽  
Emma Foos ◽  
Matthew Hitron ◽  
Warren Mason
Keyword(s):  
Antitumor Activity ◽  
Objective Response ◽  
Dose Intensity ◽  
Progression Free Survival ◽  
Phase 2 ◽  
Open Label ◽  
Antitumor Effects ◽  
Patient Reported ◽  
Phase 1B ◽  
Grade 3

Abstract Napabucasin is an orally-administered NQO1–bioactivatable investigational agent hypothesized to affect multiple oncogenic cellular pathways including STAT3. This open-label, multicenter, phase 1b/2 study assessed napabucasin plus temozolomide for recurrent/progressive GBM. Phase 1b objectives were safety/tolerability, recommended phase 2 dose (primary), preliminary antitumor activity, and pharmacokinetics/pharmacodynamics (secondary). Phase 2 objectives were preliminary antitumor activity via 6-month progression-free survival (PFS-6 [20% projected]) (primary); disease control rate; median PFS; objective response rate (ORR); and overall survival (OS) (secondary). Arm A enrolled repeat surgical resection candidates; arm B enrolled patients ineligible for further resection. Patients received napabucasin (oral, 480 mg twice-daily) plus temozolomide (150 mg/m2, days 1–5, 28-day cycles). Arm A closed after 4 patients enrolled to prioritize Arm B enrollment. Arm B data are reported. Arm B enrolled/treated 30 patients (median age=56.5 [range=19–83] years; median napabucasin duration=55.0 [range=1–743] days; previous temozolomide=22 [73.3%] patients); all stopped therapy (radiologic progressive disease [PD], n=20; clinically unacceptable toxicities, n=7; follow-up loss, n=2; clinical PD, n=1). Mean relative dose intensity was 67.2% for napabucasin and 90.9% for temozolomide; 14/30 (46.7%) and 25/30 (83.3%) patients received ≥ 90% intended napabucasin and temozolomide doses, respectively. All patients reported ≥ 1 treatment-emergent adverse event (TEAE, grade ≤4); grade 3 TEAEs (≥ 10% patients) were diarrhea (23.3%, 7/30) and abdominal pain (16.7%, 5/30). One patient reported a grade 4 TEAE (seizure, treatment unrelated). PFS-6 was 28.1% (80% CI=16.8%-40.5%). Median PFS was 1.9 months (95% CI=1.8–3.3), with PFS-12 and PFS-18 both 16.8% (80% CI=7.8%-28.8%). ORR was 10% (95% CI=2.1%-26.5%), with 3 partial responses, 6 stable disease, 14 PD, and 7 patients not evaluated. OS-12 was 28.3%. The napabucasin-plus-temozolomide safety profile was consistent with that anticipated for each agent. Napabucasin (480 mg twice-daily) was associated with grade 3 diarrhea and suboptimal compliance. Antitumor effects were observed per the primary endpoint in this patient population.

scholarly journals Phase 2 study of TAS-117, an allosteric akt inhibitor in advanced solid tumors harboring phosphatidylinositol 3-kinase/v-akt murine thymoma viral oncogene homolog gene mutations

2021 ◽  
Author(s):  
Jii Bum Lee ◽  
Minkyu Jung ◽  
Seung Hoon Beom ◽  
Gun Min Kim ◽  
Hye Ryun Kim ◽  
...  
Keyword(s):  
Adverse Events ◽  
Progression Free Survival ◽  
Phase 2 ◽  
Phosphatidylinositol 3 Kinase ◽  
Akt Inhibitor ◽  
Viral Oncogene ◽  
Phase 2 Study ◽  
Grade 3 ◽  
Viral Oncogene Homolog ◽  
Phosphatidylinositol 3

SummaryTAS-117 is a potent and selective allosteric pan-v-akt murine thymoma viral oncogene homolog (Akt) inhibitor. We conducted a single-arm single-center phase 2 study of TAS-117 in heavily treated patients with tumors refractory to systemic chemotherapy and harboring phosphatidylinositol 3-kinase (PI3K)/Akt mutations. Patients with gastrointestinal (GI) cancers were orally administered 16 mg TAS-117 daily, and those with non-GI tumors were administered 24 mg on a 4 days on/3 days off schedule. The primary endpoint was overall response rate (ORR). Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), PFS ratio, safety, and tolerability. Thirteen patients were enrolled: eight with non-GI (breast, ovarian, endometrial, and non-small cell lung) and five with GI (colon, rectal, gastric, and gallbladder) cancers. Ten patients were treated with TAS-117 after ≥ 4 lines of therapy. Twelve patients showed PIK3 catalytic subunit alpha (PIK3CA) mutations; one harbored an Akt1E17K mutation. The median treatment duration was 1.4 months; the median number of treatment cycles was 2. The ORR was 8 %, and DCR was 23 %. The median PFS and OS were 1.4 and 4.8 months, respectively. Grade 3–4 treatment-related adverse events were anorexia (grade 3, 8 %) and hyperglycemia (grade 3, 8 %; grade 4, 8 %).Grade 3–4 treatment-related adverse events occurred in 27 % of grade 3 anorexia (9 %) and hyperglycemia (grade 3, 8 %; grade 4, 9\%). TAS-117 showed limited antitumor activity and manageable toxicity. Clinical efficacy was observed in patients with ovarian cancer harboring PIK3CA E545K mutations and in patients with breast cancer harboring PIK3CA H1047R and Akt1E17K mutations.Trial registration: This study was retrospectively registered with ClinicalTrial.gov (NCT03017521 on January 11, 2017).

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