Investigation of the HDAC inhibitor resminostat in patients with sorafenib-resistant hepatocellular carcinoma (HCC): Clinical data from the phase I/II SHELTER study.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 262-262 ◽  
Author(s):  
Michael Bitzer ◽  
Marius Horger ◽  
Tom M Ganten ◽  
Jens T Siveke ◽  
Marcus A Woerns ◽  
...  
Keyword(s):  
Clinical Data ◽  
Hdac Inhibitor ◽  
Rest Period ◽  
Progression Free Survival ◽  
Primary Objective ◽  
Open Label ◽  
First Line Therapy ◽  
Parallel Group ◽  
Term Tolerability ◽  
Grade 3

262 Background: Resminostat (4SC-201), an oral pan-HDAC inhibitor, is in clinical development in a variety of cancer indications. The SHELTER study aims to evaluate safety, tolerability and efficacy in HCC patients (pts) exhibiting progressive disease under sorafenib first-line therapy. Methods: Pts with advanced HCC, (BCLC B or C) are included in a multi-center, open-label, two-arm parallel group trial. Radiologic progression under sorafenib is determined acc. to RECIST by central review prior to study entry. For Arm A, dose escalation of resminostat and sorafenib is performed to determine the MTD. Resminostat is administered orally once-daily in a “5+9” schedule, consisting of 5 consecutive treatment days followed by a 9-day rest period resulting in 14 day cycles on dose levels of 200 (DL1), 400 (DL2) and 600 mg (DL3+4), either combined with continuously taken sorafenib at 400 (DL1-3) or 800 mg (DL4) (Arm A), or as resminostat monotherapy (600 mg, Arm B). Primary objective is to determine progression-free survival after 12 weeks (w) (6 cycles). Secondary objectives include safety, tolerability, tumor response, TTP, OS, PK, biomarkers. Results: To date, 39 pts were treated with 600 mg resminostat alone or on DL1-4 in combination with sorafenib. Up to now, no DLT occurred in 5 pts treated on DL4. Most frequently AE observed include CTC grade 1-2 gastrointestinal complaints such as nausea and vomiting and skin disorders like rash, pruritus and HFSR. CTC Grade 3-4 toxicity documented in SAE reports consisted mainly of no-hematological events and was mostly related to the tumor disease. Interim results revealed that 15 out of 27 pts (56%) assessed after 6 w of treatment, and 11 out of 24 pts after 12 w displayed SD. In one patient treated on DL2, SD persisted for more than 1 year along with good long-term tolerability. Conclusions: Preliminary clinical data show a favorable drug profile of resminostat either in mono or in combination treatment with sorafenib. No DLT was observed on the highest DL of the combination therapy up to now. Initial data on toxicity and therapeutic activity to overcome resistance to sorafenib are promising and will be updated for the meeting.

Clinical update on the SHELTER study: A phase I/II trial of the HDAC inhibitor resminostat in patients with sorafenib-resistant hepatocellular carcinoma (HCC).

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 275-275 ◽  
Author(s):  
M. Bitzer ◽  
M. Horger ◽  
T. Ganten ◽  
M. P. Ebert ◽  
M. A. Woerns ◽  
...  
Keyword(s):  
Hdac Inhibitor ◽  
Rest Period ◽  
Progression Free Survival ◽  
Primary Objective ◽  
Oral Drug ◽  
Open Label ◽  
First Line Therapy ◽  
Parallel Group ◽  
Term Tolerability ◽  
Dose Levels

275 Background: Resminostat (4SC-201) is a novel oral pan-HDAC inhibitor in clinical development in a variety of cancer indications. The aim of the SHELTER study is to evaluate safety, tolerability, and efficacy in patients (pts) with HCC exhibiting progressive disease under sorafenib first-line therapy. Methods: Sorafenib-refractory pts with advanced HCC, BCLC B or C are included in a multicenter, open-label, two-arm parallel group trial. Resminostat is administered orally on three dose levels of 200 (DL1), 400 (DL2), and 600 mg (DL3) once daily, in combination with 400 mg sorafenib (arm A) or as mono therapy (600 mg, arm B). For arm A, a precedent dose escalation of resminostat and sorafenib is performed to determine the MTD. Resminostat is administered in a “5+9” dosing schedule, consisting of 5 consecutive treatment days (D1-5) followed by a 9-day rest period resulting in 14 day cycles. In arm A sorafenib is given twice daily throughout the treatment period. Primary objective is to determine progression-free survival rate after 12 weeks (6 cycles). Secondary objectives include safety and tolerability, tumor response, estimation of TTP, OS, assessment of PK, and biomarkers. Results: To date, 14 pts were treated either with 600 mg resminostat alone or on DL1-3 in combination with 400 mg sorafenib. The majority of AE observed so far include gastrointestinal disorders such as nausea and vomiting. Plasma exposure to resminostat increased dose-dependently on D1 (cycle 1) with mean AUC 0-6 h values of 10.5 h*mg/L (600 mg mono) and 9.01 h*mg/L (DL3). No major changes in PK characteristics of resminostat were found with or without co-administration of sorafenib. A considerable portion of patients showed stabilization of their disease (SD): 9 out of 12 pts and 4 out of 5 pts examined after 6 and 12 weeks, respectively, displayed SD. In one patient treated on DL2, SD persisted for 36 weeks along with good long-term tolerability. Conclusions: Preliminary clinical data confirmed the favorable oral drug profile of resminostat either in mono or in combination treatment with sorafenib. Initial data on therapeutic activity to overcome resistance to sorafenib are promising. [Table: see text]

scholarly journals Oral vinorelbine and cisplatin as first-line therapy for advanced squamous NSCLC patients: a prospective randomized international phase II study (NAVoTrial 03)

2021 ◽  
Vol 13 ◽  
pp. 175883592110229
Author(s):  
Francesco Grossi ◽  
Piotr Jaśkiewicz ◽  
Marion Ferreira ◽  
Grzegorz Czyżewicz ◽  
Dariusz Kowalski ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Ii Study ◽  
Current Knowledge ◽  
Progression Free Survival ◽  
Primary Objective ◽  
Comparable Efficacy ◽  
Open Label ◽  
Oral Vinorelbine ◽  
First Line Therapy ◽  
Nsclc Patients

Objective: The study investigated the efficacy and safety of oral vinorelbine-cisplatin (OV-CDDP) and gemcitabine-cisplatin (GEM-CDDP) in patients with squamous non-small cell lung cancer (sq-NSCLC). Patients and methods: This was an open-label, prospective, multicenter, international phase II study that enrolled untreated patients with advanced sq-NSCLC. Patients were randomized to receive 3-week cycles of either 60–80 mg/m2 OV days 1 and 8 in combination with 80 mg/m2 CDDP day 1 (arm A) or 1250 mg/m2 GEM days 1 and 8 in combination with 75 mg/m2 CDDP day 1 (arm B). After four cycles, patients without disease progression continued maintenance dose of OV or GEM until progression or unacceptable toxicity. The primary objective was disease control rate (DCR). Secondary objectives included progression-free survival (PFS), time to treatment failure (TTF), overall survival (OS), safety, and quality of life (QoL). Results: A total of 114 patients with sq-NSCLC were randomized, and 113 were treated (57 in arm A and 56 in arm B). DCR was high in both arms: 73.7% (95%CI: 62.4–100.0) in arm A and 75.0% (95%CI: 63.7–100.0) in arm B. Median PFS and TTF were similar in arm A and B 4.2 and 2.8 months, and 4.3 and 3.1 months, respectively. Even though the difference was not significant, the OS was 10.2 for arm A and 8.4 months for arm B. The safety profiles were consistent with the current knowledge of adverse events. QoL results revealed an improvement in patients under OV treatment. Conclusion: The OV-CDDP combination showed comparable efficacy to GEM-CDDP with acceptable safety profile and enhanced patients’ QoL. Trial registration: The study was registered under EudraCT number 2012-003531-40.

Vinflunine maintenance therapy versus best supportive care (BSC) after platinum combination in advanced bladder cancer: A phase II, randomized, open-label study (MAJA study)—SOGUG 2011-02.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. TPS4674-TPS4674
Author(s):  
Sonia Maciá ◽  
Jesus Garcia-Donas ◽  
Albert Font Pous ◽  
Montserrat Domenech ◽  
Xavier Garcia del Muro ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Transitional Cell ◽  
Progression Free Survival ◽  
Best Supportive Care ◽  
Primary Objective ◽  
Open Label ◽  
Microtubule Inhibitor ◽  
Translational Study ◽  
First Line Therapy ◽  
Radiological Response

TPS4674 Background: Vinflunine is a novel microtubule inhibitor currently approved by EMA as treatment after platinum progression, in metastasic bladder cancer. It is distinguished from the other vinca-alkaloids because it binds relatively weakly to tubulin, suggesting an improved tolerance profile as a result of less neuropathy. Based on the fact that no cumulative toxicity is expected and the results reported in second-line, we aim to test the role of vinflunine in first line therapy, as maintenance treatment for patients who obtain clinical benefit after platinum. Methods: This is a multicenter, randomized, open label, proof-of-concept study that will be performed in 20 institutions members of the Spanish Oncology Genitourinary Group (SOGUG). Subjects will be randomized in a 1:1 ratio to receive vinflunine 320 mg/m2 every 21 days plus BSC vs BSC alone until disease progression. Vinflunine dose will be 280mg/m2 for patients with PS=1, age ≥ 75 years, prior pelvic radiotherapy or creatinine clearance Cr <60ml/min. Stratification factors are: 1) Scheduled dose at randomization (320 vs 280mg/m2) 2) Liver metastasis (Y/N). Main inclusion criteria are: Subjects ≥18 and< 80 years of age with histological diagnosis of transitional cell carcinoma of the urothelial tract and measurable disease with radiological response or stabilization after 6 cycles of a platinum containing doublet for metastasic/advanced disease. Primary objective will be progression free survival (PFS), considering as clinically relevant 6 months in experimental arm. To guarantee an overall type-1 α error (one side) no greater than 0.05 and a type II (β) error 0.1 for the primary endpoint of PFS, a sample size of 86 patients allocated in a 1:1 ratio is planned. Recruitment is scheduled to start by February 2012. A pharmacogenomic translational study will also be conducted.

Randomized phase II study of S-1/CDDP plus TSU-68 versus S-1/CDDP in patients with advanced gastric cancer.

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 72-72
Author(s):  
Kensei Yamaguchi ◽  
Wasaburo Koizumi ◽  
Hisashi Hosaka ◽  
Yasutaka Takinishi ◽  
Norisuke Nakayama ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Growth Factor ◽  
Phase Ii ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Open Label ◽  
Parallel Group ◽  
Common Grade ◽  
Grade 3 ◽  
Endothelial Growth Factor

72^ Background: Gastric cancer (GC) is the second leading cause of cancer death in Japan as well as globally. Effective treatment of GC remains a therapeutic challenge. Although in the AVAGAST trial, bevacizumab was found to offer no survival benefit. Angiogenesis continues to be the standard treatment for GC, and thus, clinical trials on many anti-angiogenic drugs have been conducted. TSU-68 (orantinib) is an oral, angiokinase inhibitor targeting the vascular endothelial growth factor receptor 2, platelet-derived growth factor receptor β, and fibroblast growth factor receptor 1. The present study evaluated the progression-free survival (PFS) and pharmacokinetics (PK) of TSU-68 in combination with Japanese standard S-1 and cisplatin (S-1/CDDP) in patients with advanced GC. Methods: In this open-label, multicenter, randomized, controlled, parallel-group, phase II trial, patients were randomized to Arm A (S-1/CDDP) or Arm B (TSU-68 plus S-1/CDDP). All patients received oral S-1 (40-60 mg/m2) twice daily for 21 days followed by a 14 day rest plus intravenous CDDP (60 mg/m2) on Day 8, repeated every 35 days. In Arm B pts received oral TSU-68 (400 mg/dose) alone, twice daily by addition 35 days. The primary endpoint was PFS. Results: In total, 93 patients were enrolled. For Arm A [male:female ratio], n=47 [35:11]; Arm B, n=45 [30:15]; the respective median age was 63.5 and 62.0 years. The median PFS was 7.0 and 6.8 months in Arms A and B, respectively (HR, 1.23; 95%CI, 0.74 to 2.05; P=0.425); the respective response rates were 56.5% and 62.2%. The most common grade 3/4 toxicities were neutropenia (Arms A and B, 34.8% and 31.1%) and hemoglobin (Arms A and B, 26.1% and 48.9%). There were no differences in other toxicities between the 2 arms, both treatments were tolerated, and no treatment-related deaths were observed. In the PK study, although Arm B had a significantly lower plasma exposure to FT, CDHP, and Oxo compared to Arm A, the exposure to 5-FU was not different between the 2 arms. The exposure to CDDP in Arm B was significantly but slightly lower than that in arm A. Conclusions: Thus,TSU-68 plus S-1/CDDP therapy did not prolong PFS of patients with advanced GC as compared with S-1/CDDP. Clinical trial information: JapicCTI-101327.

Phase II study of alternate sunitinib schedule in patients with metastatic renal cell carinoma.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 4513-4513
Author(s):  
Eric Jonasch ◽  
Rebecca Slack ◽  
Daniel M. Geynisman ◽  
Matthew I. Milowsky ◽  
Kimryn Rathmell ◽  
...  
Keyword(s):  
Renal Cell ◽  
Response Rate ◽  
Study Drug ◽  
Progression Free Survival ◽  
Primary Objective ◽  
Term Tolerability ◽  
Grade 3 ◽  
Endpoint Data

4513 Background: Sunitinib is an antiangiogenic agent indicated for the treatment of metastatic renal cell carcinoma (mRCC). Sunitinib is given in a 4 week on, 2 week off (4/2) schedule. Significant toxicities are observed in patients in the 3rd and 4th weeks of therapy. We hypothesized that a 2 week on, 1 week off (2/1) schedule would provide improved toxicity without compromising efficacy. Methods: A multicenter, single arm study was performed, with patients initiating sunitinib 50mg on a 2/1 schedule. Schedule and dose alterations were performed if grade > 3 toxicities were observed. The primary objective was to determine the percentage of patients who experienced grade > 3 fatigue, diarrhea, or HFS. The sample size of 60 patients was selected to ensure the upper bound of a 95% confidence would fall below standard schedule rate of 25%-30% if sample rate was 10%-15%, respectively. Secondary outcomes included response rate (RR), progression free survival (PFS) and dose reductions. Results: Between August 2014 and April 2016, 60 patients were enrolled, and 59 treated. Patients had a median age of 65.5 years (ranging from 45-92). 24% of patients (14/59) had grade 3 or higher fatigue, diarrhea, or HFS (95% CI: 13.6%, 36.6%). This is similar to the average of the 4 week on, 2 week off schedule of 25%-30%, and the lower bound of the confidence interval is in the center of our target rate of 10%-15%. Among events at least possibly related to study drug, patients were most likely to experience the expected events of diarrhea (75% with 5 grade 3 events), fatigue (71% with 6 grade 3 events), and HFS (54% with 3 grade 3 events). 22 (37%) patients responded (25.0%, 50.9%). Among patients with secondary endpoint data available, median PFS was 19.3 months (95% CI: 8.2, NR) and 33/56 (59%) of patients underwent dose reduction. Conclusions: Sunitinib administered in a 2/1 schedule in this study did not result in a lower rate of grade 3 or higher fatigue, diarrhea or HFS when compared to historical data from trials employing a 4/2 schedule. However, efficacy data showed robust response rate and a prolonged PFS, suggestive of long-term tolerability in patients receiving sunitinib on a 2/1 schedule. Evaluation of toxicity kinetics and patient quality of life is ongoing. Clinical trial information: NCT02060370.

Phase II study of S-1 in patients with gemcitabine resistant advanced pancreatic carcinoma

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 14070-14070 ◽  
Author(s):  
K. Sudo ◽  
T. Yamaguchi ◽  
T. Ishihara ◽  
K. Nakamura ◽  
H. Saisho
Keyword(s):  
Pancreatic Carcinoma ◽  
Performance Status ◽  
Rest Period ◽  
Progression Free Survival ◽  
Primary Objective ◽  
Ecog Performance Status ◽  
Eligibility Criteria ◽  
Advanced Pancreatic Carcinoma ◽  
Grade 3 ◽  
Ecog Ps

14070 Background: S-1 is an oral fluoropyrimidine derivative with reported response rate of 21.1∼37.5% for advanced pancreatic carcinoma (Ueno, Oncology 2005; Furuse, ASCO 2005). The primary objective of this study was to assess the efficacy and safety of S-1 in patients with gemcitabine resistant advanced pancreatic carcinoma. Methods: Patients with histologically or cytologically proven, metastatic pancreatic carcinoma who had failed prior chemotherapy with gemcitabine were eligible for this study. Other eligibility criteria included an ECOG performance status (PS) of 2 or less; an age of at least 20 years; adequate organ function; and written informed consent. S-1 was administered orally at a dose of 40 mg/m2 twice daily for 28 days, followed by a 14-day rest period. Treatment was repeated every 6 weeks until disease progression. Results: Seventeen patients were enrolled with the following characteristics: median age 67 (range 40–75); male/female = 9/8; ECOG PS 0/1/2 = 1/8/8. All patients were included in analysis. Treatment was generally well tolerated and no life threatening toxicity was observed. Grade 3–4 toxicities were anorexia (17.6%) and fatigue (5.9%). Common grade 1–2 toxicities were anorexia (35.3%), anemia (35.3%), leukocytopenia (29.4%) and diarrhea (23.5%). Three patients were discontinued S-1 because of toxicities. Out of the 17 eligible patients, 3 patients (17.6%) achieved a partial response and 5 patients (29.4%) had stable disease. A marked decrease (≥50%) in tumor markers was observed in 5 (29.4%) of the patients. (CA 19–9 in 3 patients, CEA in 1 patient, DUPAN-2 in 1 patient) The median progression-free survival and the median survival time from the date of initiation of S-1 were 4.1 months (95% CI, 2.0 to 6.2 months) and 5.7 months (95% CI, 2.6 to 8.7 months), respectively. Conclusions: S-1 is well tolerated and active in patients with gemcitabine resistant advanced pancreatic carcinoma. Further investigation of this treatment appears warranted. No significant financial relationships to disclose.

Dose-ranging study of the combination of paclitaxel poliglumex and pemetrexed in advanced non-small cell lung cancer (NSCLC)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e19090-e19090
Author(s):  
B. M. Slagle ◽  
J. R. Rigas ◽  
K. H. Dragnev ◽  
I. Williams ◽  
W. DiSalvo ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Dose Level ◽  
Advanced Nsclc ◽  
Performance Status ◽  
Progression Free Survival ◽  
Primary Objective ◽  
Open Label ◽  
Prior Chemotherapy ◽  
Dose Ranging ◽  
Grade 3

e19090 Background: Taxanes continue to play an important role in the treatment of advanced NSCLC. Paclitaxel poliglumex (XyotaxTM) is an ester α-poly-L-glutamic acid conjugate of paclitaxel allowing for solubility in aqueous solution, not requiring Cremophor or ethanol for intravenous administration or premedications. This is a non-randomized single-arm, single-institution open label dose-ranging study was designed to evaluate the combination of pemetrexed and paclitaxel poliglumex. Methods: The primary objective of this study was to evaluate the safety of this combination. Patients (pts) were enrolled in 2 different dosing levels. The first 6 received 135 mg/m2 paclitaxel poliglumex and 500 mg/m2 pemetrexed intravenously every 3 wks. None of the 6 pts experienced an initial dose limiting toxicity (IDLT) following 2 cycles of therapy and the paclitaxel poliglumex was then escalated to 175 mg/m2 with 500 mg/m2 pemetrexed. Eligibility included advanced NSCLC, one or more measurable lesions (RECIST), ECOG = 0–2, prior chemotherapy and radiation allowed, no grade 2+ peripheral neuropathy, no untreated brain metastases, and no active cardiac disease. Results: Twelve pts were enrolled, 6 pts to each dose level. Four of the pts were female, the median age was 65 years (48- 74), 11 had a performance status of 0–1, and only 1 pt received prior chemotherapy. There were no IDLTs at the first dose level, and there was one IDLT of infection with neutropenia at the second dose level. The median number of cycles completed was 5 (range 1–12 cycles). Aside from grade 3 fatigue in 2 pts there were no grade 3 or greater non-hematologic toxicities. Common non-hematologic toxicities included peripheral neuropathy, constipation, fatigue, and alopecia. Of the 12 pts, the best response was stable disease in 9 pts, 2 are without disease progression, and 6 pts are alive to date. The median progression free survival was 3.3 months (range 0.7–10.7 months). Conclusions: The combination of paclitaxel poliglumex and pemetrexed was well tolerated at the proposed phase II dose of 175 mg/m2 and 500 mg/m2. The PFS is encouraging and future studies of this combination are recommended. No significant financial relationships to disclose.

Safety results of the Canadian Expanded Access Program (EAP) of palbociclib (PAL) plus letrozole (L) in postmenopausal patients (pts) with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) deemed appropriate candidates for first-line (1L) endocrine therapy (ET) with L.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e12534-e12534
Author(s):  
Anil A. Joy ◽  
Shailendra Verma ◽  
Louise Provencher ◽  
Kathy Puyana Theall ◽  
Dongrui (Ray) Lu ◽  
...  
Keyword(s):  
Growth Factor Receptor ◽  
Study Drug ◽  
Progression Free Survival ◽  
Primary Objective ◽  
Open Label ◽  
Hormone Receptor Positive ◽  
Patient Reported ◽  
Scale Scores ◽  
Grade 3 ◽  
Metastatic Sites

e12534 Background: In the PALOMA-2 study, 1L PAL+L prolonged progression-free survival in women with estrogen receptor-positive/HER2- ABC vs placebo + L (hazard ratio 0.58; P< 0.001). Here we assess a cohort of Canadian pts treated with 1L PAL+L for ABC in an EAP study (NCT02142868). Methods: This was an open-label, single-arm study of US and Canadian postmenopausal women (N = 337) with HR+/HER2- ABC for whom 1L ET with L was deemed appropriate. The primary objective was to allow pt access to PAL in combination with L. PAL (125 mg/d orally [3 wk on, 1 wk off]) was administered with L (2.5 mg orally QD) until PAL was commercially available. Secondary objectives included safety and patient-reported outcomes (PROs). Results: 96/97 (99%) treated/enrolled Canadian pts were assessed for safety and PROs (treated pt characteristics: median age 62.5 y, white/Asian [89%/7%], metastatic sites bone/lung/liver [71%/25%/17%], ECOG PS 0-1/2 [93%/7%], 89% with prior systemic anticancer treatment [tx]). Median exposure was 4 x 28 d cycles of tx, and the median average PAL dose was 125 mg/d. All-causality treatment-emergent adverse events (AEs) were reported in 100% pts; 68% had grade 3/4 events, the most common events were neutropenia (61%), infections (3%), and alanine aminotransferase increase (3%). Grade 4 neutropenia and grade 3 febrile neutropenia were reported in 2% and 1% of pts, respectively. Due to AEs, PAL was temporarily discontinued in 59% and 31% had ≥1 dose reduction. The main reasons pts permanently discontinued from the study were sponsor study termination, 77%; objective progression, 11%; and AE related/unrelated to study drug, 6%/2%. All EQ-5D questions were completed by 96% pts at baseline and 85% by end of tx (EOT). At EOT, the median EQ-5D index and the EQ visual analog scale scores were not significantly changed from baseline. Conclusions: A safe and tolerable profile was observed for PAL+L in 1L treatment of Canadian pts with HR+/HER2− ABC, consistent with other studies. Sponsor Pfizer Clinical trial information: NCT02142868.

Adavosertib with chemotherapy (CT) in patients (pts) with platinum-resistant ovarian cancer (PPROC): An open label, four-arm, phase II study.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 5513-5513 ◽  
Author(s):  
Kathleen N. Moore ◽  
Setsuko K. Chambers ◽  
Erika Paige Hamilton ◽  
Lee-may Chen ◽  
Amit M. Oza ◽  
...  
Keyword(s):  
Objective Response ◽  
Pegylated Liposomal Doxorubicin ◽  
Progression Free Survival ◽  
Dose Schedule ◽  
Primary Objective ◽  
Hematologic Toxicity ◽  
Open Label ◽  
Free Survival ◽  
Common Grade ◽  
Grade 3

5513 Background: Adavosertib (AZD1775; A), a highly selective WEE1 inhibitor, demonstrated activity and tolerability in combination with carboplatin (C) in primary PROC. This study (NCT02272790) assessed the objective response rate (ORR) and safety of A in PROC. Methods: Pts with recurrent RECIST v1.1 measurable PROC received A with C, gemcitabine (G), weekly paclitaxel (P), or pegylated liposomal doxorubicin (PLD) in 3- (C) or 4-week (G, P, PLD) cycles (Table). Tumor assessments were performed every 2 cycles until disease progression. Primary objective: ORR; other objectives: disease control rate (DCR), progression-free survival (PFS) and safety. Results: In the 94 pts treated (median treatment duration 3 months; range 0–16 months), outcomes were greatest with A (weeks [W]1–3) + C (Table), with ORR of 67% and median PFS (mPFS) of 10.1 months for this cohort. Most common grade ≥3 treatment-emergent adverse events (TEAEs) are shown in the Table, with hematologic toxicity most notable with A (W1–3) + C. TEAEs led to A dose interruptions, reductions and discontinuations in 63%, 30% and 13% of the whole cohort, respectively. A possible positive relationship between CCNE1 amplification and response warrants further investigation. Conclusions: A shows preliminary efficacy when combined with CT. Pts receiving A (W1–3) + C showed greatest benefit. The increased but not unexpected hematologic toxicity is a challenge and could be further studied to optimize the dose schedule and supportive medications. Clinical trial information: NCT02272790. [Table: see text]

SAVOIR: A phase III study of savolitinib versus sunitinib in pts with MET-driven papillary renal cell carcinoma (PRCC).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 5002-5002
Author(s):  
Toni K. Choueiri ◽  
Daniel Yick Chin Heng ◽  
Jae-Lyun Lee ◽  
Mathilde Cancel ◽  
Remy B Verheijen ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Randomized Study ◽  
Objective Response ◽  
Progression Free Survival ◽  
Primary Objective ◽  
Chromosome 7 ◽  
Phase Iii ◽  
Open Label ◽  
Grade 3 ◽  
Dose Modifications

5002 Background: PRCC is the most common type of non-clear cell RCC, accounting for 10–15% of renal malignancies. As a subset of PRCC cases are MET-driven, MET inhibition may be an appropriate targeted treatment approach. In a single-arm Phase II study, savolitinib (AZD6094, HMPL‐504, volitinib), a highly selective MET-tyrosine kinase inhibitor, demonstrated antitumor activity in pts with MET-driven PRCC (Choueiri et al. JCO 2017). The Phase III SAVOIR study (NCT03091192) further assessed savolitinib vs standard of care sunitinib in pts with MET-driven PRCC. Methods: In this open-label (sponsor blinded), randomized study, pts with centrally confirmed MET-driven ( MET and/or HGF amplification, chromosome 7 gain and/or MET kinase domain mutations), metastatic PRCC were randomized to savolitinib 600 mg once daily (QD), or sunitinib 50 mg QD 4 weeks on / 2 weeks off. Primary objective was progression-free survival (PFS; RECIST 1.1 by blinded independent central review). Secondary objectives included overall survival (OS), objective response rate (ORR), and safety and tolerability. Results: After external data on predicted PFS with sunitinib in pts with MET-driven disease became available, study enrollment was closed. At data cutoff (Aug 2019), only 60 of the planned 180 pts were randomized (savolitinib n = 33; sunitinib n = 27). Most had chromosome 7 gain (savolitinib 91%; sunitinib 96%) and no prior therapy (savolitinib 85%; sunitinib 93%). PFS, OS, and ORR were numerically improved with savolitinib vs sunitinib (Table). CTCAE grade ≥3 adverse events (AEs) were reported in 42% and 81% of pts; dose modifications were related to AEs in 30% and 74% of pts with savolitinib and sunitinib respectively. After discontinuation, 36% of all savolitinib and 19% of all sunitinib pts received subsequent anticancer therapy. Conclusions: Although pt numbers and follow-up were limited, savolitinib demonstrated encouraging efficacy and an improved safety profile vs sunitinib, with fewer grade ≥3 AEs and fewer dose modifications required. Sunitinib performance was poorer than expected based on external retrospective data. Further investigation of savolitinib as a treatment option for MET-driven PRCC is warranted. Clinical trial information: NCT03091192 . [Table: see text]

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