Phase II study of dovitinib in first-line metastatic or nonresectable primary adrenocortical carcinoma (ACC): SOGUG study 2011-03.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. TPS4688-TPS4688
Author(s):  
Paula Jimenez ◽  
Marta Guix ◽  
Nuria Lainez Milagro ◽  
Luis Leon Mateos ◽  
Maria Jose Mendez Vidal ◽  
...  
Keyword(s):  
Phase Ii ◽  
Type I Error ◽  
Sample Size Calculation ◽  
Growth Factor Receptor ◽  
Collaborative Group ◽  
Type I ◽  
Open Label ◽  
Prior Therapy ◽  
Power Of The Test ◽  
Open Label Phase

TPS4688 Background: Dovitinib is a novel targeted therapy, that has proven to inhibit, among other tyrosin kinases, the fibroblast growth factor receptor (FGFR). Since this pathway has been proposed to play a major role in ACC, we aim to test the clinical efficacy of dovitinib in this tumor. Methods: An open label phase II trial has been designed in patients with advanced non-resectable ACC. The objective will be to obtain at least a 15% response rate according to RECIST criteria. Taking as a basis the two-stage Gehan model, 15 patients would need to be included in the first stage to demonstrate a treatment efficacy of at least 15%. Sample size calculation was done based on the following parameters, probability of Type I error α = 0.05, power of the test (1 - β) = 0.8. Main inclusion criteria are advanced non-resectable disease and no prior therapy (other than mitotane). Dovitinib scheduled dose matches currently employed standard in the drug development (500mg daily for 5 days then 2 days off) for 6 months. If clinical benefit is obtained longer treatment will be allowed for particular patients. Since this is an extremely unfrequent disease 7 institutions, members of the SOGUG (Spanish Oncology Genitourinary Group), will participate. The active support of a big collaborative group will guarantee candidate patients to be refereed to such institutions. Starting January 26th 2012 recruitment is scheduled to last around 12 months. A translational research, including whole exome analysis, will be performed in order to improve our scarce knowledge of ACC.

Phase II study of dovitinib in first line metastatic or (nonresectable primary) adrenocortical carcinoma (ACC): SOGUG study 2011-03.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 4587-4587 ◽  
Author(s):  
Jesús García-Donas ◽  
Susana Hernando Polo ◽  
Marta Guix ◽  
Miguel Angel Climent Duran ◽  
Maria Jose Mendez Vidal ◽  
...  
Keyword(s):  
Disease Progression ◽  
Phase Ii ◽  
Stable Disease ◽  
Adrenocortical Carcinoma ◽  
Clinical Benefit ◽  
Type I Error ◽  
Objective Response ◽  
Sample Size Calculation ◽  
Growth Factor Receptor ◽  
Type I

4587 Background: Dovitinib is a novel targeted therapy that inhibits the fribroblast growth factor receptor (FGFR). Preclinical studies have pointed to a major role of this pathway in adrenocortical carcinoma (ACC) thus we aimed to test its clinical efficacy in this tumor. Methods: A phase II proof of concept trial was designed. Since this is an extremely infrequent disease sample size calculation was done taking as a basis the first stage of a two-stage Gehan model. Thus 15 patients needed to be included to show a treatment efficacy of at least 15% (probability of Type I error α = 0.05, power [1 – β] = 0.8). Main inclusion criteria was advanced non-resectable ACC, histologically confirmed, with no prior therapy other than mitotane. Primary endpoint was response rate (RR) by RECIST 1.1 assessed by an independent radiologist. Secondary endpoints included clinical benefit (RR plus stable disease), progression free (PFS) and overall survival (OS). Dovitinib was administered at 500mg daily dose 5 days on 2 days off for 6 months. Continuation of therapy was permitted at physician criteria. Results: From January 2012 to August 2012, 17 patients (5 male and 12 female) have been included in 7 institutions. Median age was 53 years (range 26-72); ECOG was 0-1 in 15 patients, 2 in one patient and N/A in one patient. 77 cycles, defined as one month on treatment, have been administered with dose reductions in 6 (7.8%). Grade 3-4 adverse events deemed as related to the drug were: rash (6%), asthenia (12%), diarrhea (6%), GGT elevation (18%), nausea (6%), hypertriglyceridemia (6%), hypertension (6%), hyperkalemia (6%). 13 patients withdrew treatment because of disease progression and 4 remain on dovitinib. No toxic death was reported. After a median follow-up of 5, 2 months (range 2,27 – 9,7) no objective response has been observed. Median PFS was 1,8 months (CI 95% [ 1,35 -2,25]), median OS has not been reached and clinical benefit has been achieved in 35% of patients with long lasting stable disease (>6 months) in 23%. Conclusions: Though no objective response was observed, a significant number of long lasting stabilizations have been achieved with an acceptable toxicity. These encouraging results merit further study. Clinical trial information: NCT01514526.

scholarly journals OS4.1 MEVITEM: A European, randomized, open-label, Phase I/II study of vismodegib in combination with temozolomide versus temozolomide alone in adult patients with recurrent or refractory medulloblastoma presenting an activation of the Sonic Hedgehog (SHH) pathway

2019 ◽  
Vol 21 (Supplement_3) ◽  
pp. iii10-iii10
Author(s):  
D Frappaz ◽  
M Barritault ◽  
L Montané ◽  
F Laigle-Donadey ◽  
O Chinot ◽  
...  
Keyword(s):  
Sonic Hedgehog ◽  
Type I Error ◽  
Single Agent ◽  
Objective Response ◽  
Progression Rate ◽  
Type I ◽  
Filamin A ◽  
Open Label ◽  
Shh Pathway ◽  
Open Label Phase

Abstract BACKGROUND Vismodegib (V) suppresses sonic hedgehog (SHH) signaling. We postulated that vismodegib together with chemotherapy may be more efficient than chemotherapy alone in patients (pts) relapsing of a SHH-activated medulloblastoma (MB). MATERIAL AND METHODS Adult pts with recurrent SHH-MB not previously exposed to temozolomide (T) were randomly assigned (2:1 ratio) to Arm A (V daily 150mg/d, po) + T (D1-5: 150 mg/m2 for cycle 1 and 200 mg/m2 thereafter; n=up to 25pts) or Am B (T alone; n=up to 13pts). Identification of SHH activation was performed centrally by IHC (GAB1, β-catenin, filamin A, and YAP1). NGS analyses were performed to identify the mutations responsible for SHH activation. Primary objectives were to assess the incidence of severe toxicities (safety run-in based on a 3 + 3 design) and the 6-month non-progression rate (NPR-6m) according to WHO criteria and based on central read tumor assessment (Phase II). A Minimax Simon’s two-stage design was used to detect NPR-6m of 55% (p0: 30%, type I error rate of 5%, power of 80%). At first stage, ≥ 3/9 pts without progression at 6m were required for the accrual of 16 additional pts in Arm A. A 3rd independent and parallel arm with V as single agent (Arm C, n= up to15pts) was added for pts previously treated by T. RESULTS 24 SHH-MB pts were enrolled (Arm A: 10, Arm B: 5 and Arm C: 9; median age: 37 y [21–55]). At the end of the safety run-in; no major safety concerns were reported. At the end of Stage I: no objective response were reported and 2 pts among 10 were free of progression at 6m among in Arm A. According to statistical rules, the study was definitively closed to enrolment. NGS analyses showed a PTCH1 inactivating mutation in 6 pts (n=4 in arm A; n= 2 in arm B); a SMO activating mutation in 4 pts (n= 3 in Arm A; n=1 in Arm B). For 1 pt in each arm, no tumor sample was available for analysis, for 1 pt in Arm A DNA quality was insufficient, and for 1 patient in each arm no mutations of SMO, PTCH1, SUFU or SHH were found. Out of the 4 pts in Arm A with an inactivating PTCH1 mutation, only 1 was progression free at 6m. PFS and OS data will be presented at the meeting. CONCLUSION The combination of vismodegib with monthly T failed to demonstrate superior activity as compared with T alone. Further studies are warranted to refine therapeutic indication for vismodegib

scholarly journals Randomized, Open-Label Phase II Study Evaluating the Efficacy and Safety of Talimogene Laherparepvec in Combination With Ipilimumab Versus Ipilimumab Alone in Patients With Advanced, Unresectable Melanoma

2018 ◽  
Vol 36 (17) ◽  
pp. 1658-1667 ◽  
Author(s):  
Jason Chesney ◽  
Igor Puzanov ◽  
Frances Collichio ◽  
Parminder Singh ◽  
Mohammed M. Milhem ◽  
...  
Keyword(s):  
Phase Ii ◽  
Objective Response Rate ◽  
Response Rate ◽  
Phase Ii Study ◽  
Objective Response ◽  
Talimogene Laherparepvec ◽  
Open Label ◽  
Prior Therapy ◽  
End Point ◽  
Open Label Phase

Purpose We evaluated the combination of talimogene laherparepvec plus ipilimumab versus ipilimumab alone in patients with advanced melanoma in a phase II study. To our knowledge, this was the first randomized trial to evaluate addition of an oncolytic virus to a checkpoint inhibitor. Methods Patients with unresectable stages IIIB to IV melanoma, with no more than one prior therapy if BRAF wild-type, no more than two prior therapies if BRAF mutant, measurable/injectable disease, and without symptomatic autoimmunity or clinically significant immunosuppression were randomly assigned 1:1 to receive talimogene laherparepvec plus ipilimumab or ipilimumab alone. Talimogene laherparepvec treatment began in week 1 (first dose, ≤ 4 mL × 106 plaque-forming units/mL; after 3 weeks, ≤ 4 mL × 108 plaque-forming units/mL every 2 weeks). Ipilimumab (3 mg/kg every 3 weeks; up to four doses) began week 1 in the ipilimumab alone arm and week 6 in the combination arm. The primary end point was objective response rate evaluated by investigators per immune-related response criteria. Results One hundred ninety-eight patients were randomly assigned to talimogene laherparepvec plus ipilimumab (n = 98), or ipilimumab alone (n = 100). Thirty-eight patients (39%) in the combination arm and 18 patients (18%) in the ipilimumab arm had an objective response (odds ratio, 2.9; 95% CI, 1.5 to 5.5; P = .002). Responses were not limited to injected lesions; visceral lesion decreases were observed in 52% of patients in the combination arm and 23% of patients in the ipilimumab arm. Frequently occurring adverse events (AEs) included fatigue (combination, 59%; ipilimumab alone, 42%), chills (combination, 53%; ipilimumab alone, 3%), and diarrhea (combination, 42%; ipilimumab alone, 35%). Incidence of grade ≥ 3 AEs was 45% and 35%, respectively. Three patients in the combination arm had fatal AEs; none were treatment related. Conclusion The study met its primary end point; the objective response rate was significantly higher with talimogene laherparepvec plus ipilimumab versus ipilimumab alone. These data indicate that the combination has greater antitumor activity without additional safety concerns versus ipilimumab.

Interim analysis of IMMUNEBOOST-HPV: A multicenter, randomized, open label, phase II study evaluating the feasibility, and tolerance of neoadjuvant nivolumab in high-risk HPV driven oropharynx cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 6037-6037
Author(s):  
Haitham Mirghani ◽  
Caroline Even ◽  
Alicia Larive ◽  
Jerome Fayette ◽  
Karen Benezery ◽  
...  
Keyword(s):  
Type I Error ◽  
Data Monitoring Committee ◽  
Smoking History ◽  
Type I ◽  
Open Label ◽  
Hpv Dna ◽  
Neoadjuvant Immunotherapy ◽  
Open Label Phase ◽  
High Risk Hpv ◽  
Type 2 Error

6037 Background: Among HPV-positive Oropharyngeal Cancer (OPC) patients (pts), some has a less favorable prognosis (T4, N2/N3, smokers >10 pack-year [p/y]). We assume that neoadjuvant immunotherapy might improve their oncological outcomes, so we tested nivolumab (N) prior to ChemoRadiaTion (CRT). Methods: The study population is restricted to HPV positive OPC pts (both p16+ & HPV-DNA+) with advanced disease (T4, N2/N3) or a smoking history >10 p/y. Pts were randomly allocated 1:2 to receive either cisplatin-based CRT (n=20) or 2 cycles of N 240 mg followed by CRT (n=41). The Primary Endpoint (PE) is the rate of pts who can receive Full Treatment in Due Time (FTDT), according to these criteria: a) 2 N infusions on day 1 and on day 14-16 b) CRT started between days 28-37 after the 1st N infusion c) No RT break ≥1 week d) RT dose received >95% of theoretical dose e) Cisplatin dose received ≥200 mg/m² To achieve FTDT, all criteria are required in the Experimental Arm (EA) while only criteria c), d), and e) are required in the Control Arm (CA). In the EA, the trial was designed in 2 steps, with FTDT rate of 88% considered as inacceptable versus an alternative of 98%, a type I error of 0.10, and a type 2 error of 0.08. As per protocol, patient accrual was temporarily suspended after inclusion of 19 pts in the EA (1st step) and results were reviewed by an Independent Data Monitoring Committee (IDMC). To resume pts’ inclusion, FTDT had to be achieved in 18 pts in the EA. Results: From 07/2019 to 09/2020, 30 pts were enrolled including 11 in the CA (demographics are summarized in table). 2 pts in the EA did not reach the PE. For the 1st patient, the cisplatin dose was <200 mg/m2 due to grade 1 hearing loss and grade 2 tinnitus (1st cycle: 100 mg/m2, 2nd cycle: 80 mg/m2, no 3rd cycle). For the 2nd patient, CRT began at D38 due to logistical issues (maintenance of RT devices). As this delay was unrelated to N or to patient's condition, the IDMC considered that the inclusions could resume for the 2nd step. 7 N-related Adverse Events (AE) were reported in 4 pts including 3 serious AE (ankylosing spondylitis flare-up, colitis, diabetic ketoacidosis). Conclusions: Neoadjuvant N before CRT seems feasible for the treatment of OPC pts. The trial has reopened to inclusion as recommended by the IDMC. Clinical trial information: NCT03838263. [Table: see text]

Capecitabine (X) compared to X + erlotinib (E) as first-line treatment in patients (pts) with metastatic colorectal cancer (MCRC): Interim efficacy results from a randomized phase II study

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 14560-14560 ◽  
Author(s):  
M. Vincent ◽  
I. Kerr ◽  
B. Dingle ◽  
M. J. MacKenzie ◽  
M. Sanatani
Keyword(s):  
Phase Ii ◽  
Phase Ii Study ◽  
Growth Factor Receptor ◽  
First Line ◽  
Open Label ◽  
Dry Eyes ◽  
Open Label Phase ◽  
Grade 3 ◽  
Ecog Ps

14560 Background: The oral fluoropyrimidine X (Xeloda®) has efficacy, safety and convenience benefits vs. 5-FU/LV in adjuvant / first-line CRC. E (Tarceva®) inhibits epidermal growth factor receptor (EGFR), which predicts poor prognosis. A randomized open-label phase II study was performed to establish activity of X alone vs. X + E (XE) in first-line. Methods: Pts (ECOG PS 0–2 and/or elevated LDH) with MCRC not eligible for immediate surgical metastatectomy and unwilling/unable to undergo combination chemotherapy were randomized to X (1000mg/m2/d bid d1–14 q3w) or XE (X 1000mg/m2/d bid d1–14 q3w + E 150mg/d). A third arm (E alone) was included but dropped after 13 pts, following safety committee review of progressions at first CT scan. Primary endpoint: time to progression (TTP). Results: 59 pts (median age 65y, range 46–84; 44 M, 15 F) have been accrued (X=21; XE=25; E=13). Mean time on study: 3.8 months (range 0.2–12). 9 pts are on active treatment, 21 pts on follow-up and 29 pts have died. Interim efficacy results are available for 50 pts (X n=15; XE n=22, E n=13). There were no significant differences in response rate, median TTP (4.9 vs. 9.2 months) and median overall survival (18.2 vs. 15.1 months) for X vs. XE. Grade 3 adverse events (AEs) with X were diarrhea, nausea, hand-foot syndrome (HFS), angina, dyspnea (all 5%). Corresponding rates of grade 3 AEs with XE were diarrhea (20%), fatigue (16%), stomatitis (12%), HFS (8%), vomiting (8%), dehydration (8%), thrombosis, weight loss, decreased appetite, dry eyes, headache, anxiety, abdominal pain, anorexia, hyponatremia (all 4%). The only grade 4 AEs were skin rash (4%) and subjective weakness (4%) - both XE. Conclusions: Interim results indicate that XE is at least as effective as X alone in first-line MCRC. Recruitment is continuing and further follow-up may help fully determine the potential benefits of adding E to X. [Table: see text] No significant financial relationships to disclose.

Efficacy and safety of panobinostat (LBH-589), a histone-deacetylase inhibitor (HDACi), in patients (pts) with advanced, previously treated soft tissue sarcoma (STS) and sex cord tumors (SCT): A study from the French Sarcoma Group.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 10027-10027 ◽  
Author(s):  
Philippe Alexandre Cassier ◽  
Anne Lefranc ◽  
Nicolas Penel ◽  
Christine Chevreau ◽  
Binh Bui Nguyen ◽  
...  
Keyword(s):  
Phase Ii ◽  
Type I Error ◽  
Treatment Options ◽  
Median Number ◽  
Type I ◽  
Phase Ii Trials ◽  
Open Label ◽  
End Point ◽  
Best Response ◽  
Grade 3

10027 Background: Treatment options are limited for pts with advanced pretreated STS. HDACi have shown activity in preclinical models of STS and SCT Methods: Pts with advanced pretreated STS and SCT were enrolled in this open label, single arm, multicenter phase II study. Panobinostat was given orally, 40 mg thrice per week. The primary end-point was 3-month progression-free rate according to RECIST 1.1 using central review. Fleming-A’Hern single-stage design for phase II trials was used, and assuming a type I error alpha of 5% with 90% power, 15/47 pts were needed to be progression free at 3 months to reject a rate of 20%. Results: Fifty three pts were enrolled between January 2010 and January 2011. Median age was 59 (range 21-79) years, and 22 (42%) pts were males, 13 had translocation-related sarcoma (TRS) and 4 had SCT. All but 5 pts had metastatic disease. The most common sites were the lung and the liver. All but one pt had documented disease progression prior to study entry. The median number of prior lines of therapy was 2 (range 1-7). Panobinostat dose was lowered to 20 mg thrice a week after 11 pts were enrolled based on the recommendation of an independent safety committee. Fifty-two pts were evaluable for toxicity (1 pt never received treatment), 48 pts (92%) reported at least one adverse event (AE) and 22 (42%) reported at least one treatment-related grade 3 or 4 AE. The most common grade 3/4 AEs were thrombocytopenia, fatigue and anemia. Fifty pts were evaluable for the primary end-point, of these, 12 pts (24%, 95%CI[13-38%]) were progression-free at 3 months, including 4/13 pts (31%, 95%CI[9-61%]) with TRS and 2/4 pts (50%, 95%CI[7-93%]) with SCT. No CR was seen, two patients (4%) with SCT had a PR and 19 pts (37%) had SD as their best response. Seven pts were progression-free at 6 months: 2 pts with SCT, 2 with TRS, 1 with liposarcoma, 1 with malignant solitary fibrous tumor and 1 with leiomyosarcoma. Conclusions: Panobinostat was poorly tolerated at 40 mg thrice a week. Efficacy in unselected advanced STS was limited although some patients had prolonged SD. Activity in pts with SCT warrants further investigation.

Safety and efficacy of pemigatinib plus pembrolizumab combination therapy in patients (pts) with advanced malignancies: Results from FIGHT-101, an open-label phase I/II study.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3606-3606
Author(s):  
Martin Gutierrez ◽  
Vivek Subbiah ◽  
John J. Nemunaitis ◽  
Niharika B. Mettu ◽  
Kyriakos P. Papadopoulos ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Phase 1 ◽  
Growth Factor Receptor ◽  
Dose Finding ◽  
Open Label ◽  
Prior Therapy ◽  
Advanced Malignancies ◽  
Open Label Phase ◽  
Cell Death Protein ◽  
Clinical Trial Information

3606 Background: Pemigatinib (INCB054828) is a selective fibroblast growth factor receptor (FGFR) 1–3 inhibitor with demonstrated efficacy as monotherapy in phase 1/2 (FIGHT-101) and phase 2 (FIGHT-201, -202, -203) trials in pts with advanced cancer. Here, we present preliminary safety, efficacy, and pharmacokinetic (PK) data for pemigatinib (PEMI) combined with pembrolizumab (PEMBRO), a programmed cell death protein-1 (PD-1) inhibitor, in pts with refractory advanced malignancies enrolled in the ongoing FIGHT-101 trial (NCT02393248). Methods: FIGHT-101 includes monotherapy (part 1 and 2) and combination therapy (part 3) cohorts. This analysis is based on pts enrolled in the PEMI + PEMBRO combination dose finding (3a) and dose expansion (3b) cohorts. Eligible adults had advanced malignancies who had progressed after prior therapy and for whom PEMBRO treatment was relevant; pts in part 3b had FGF/FGFR alterations. Pts received oral PEMI at 9 mg or 13.5 mg QD on an intermittent dosing (ID) schedule (21-day cycle, 14-day on/7-day off), or 13.5 mg QD on a continuous dosing (CD) schedule, plus PEMBRO 200 mg IV on day 1 of each 21-day cycle. Results: At data cutoff (August 30, 2019), 23 pts had received PEMI + PEMBRO; 22 (96%) had discontinued therapy (disease progression, 70%). Most frequent tumors were NSCLC (n = 3), bladder (n = 3), pancreatic, testicular, and sarcoma (each n = 2). Of 19 enrolled pts with baseline FGF/FGFR data; 5 had FGFR mutations or rearrangements. No dose-limiting toxicities occurred with PEMI + PEMBRO. The recommended PEMI dose combined with PEMBRO was 13.5 mg QD. Most frequent all-cause, all-grade (Gr) adverse events for ID (n = 17) were hyperphosphatemia (n = 14 [82%]; Gr ≥3, n = 0), anemia (n = 9 [53%]; Gr ≥3, n = 3 [18%]), and decreased appetite (n = 9 [53%]; Gr ≥3, n = 0); for CD (n = 6), hyperphosphatemia (n = 5 [83%]; Gr ≥3, n = 0), and dry mouth (n = 4 [67%]; Gr ≥3, n = 0). One pt discontinued, 2 reduced dose, and 13 interrupted dose due to AEs (none for hyperphosphatemia; dose interruption mainly for gastrointestinal AEs [n = 5]). One fatal AE occurred (suicide, not treatment-related). PK parameters for PEMI in the PEMI + PEMBRO combination were comparable with those for PEMI monotherapy. Five pts had partial response (3 had FGFR rearrangements or mutations); 5 pts had stable disease. Conclusions: PEMI + PEMBRO combination therapy was tolerable with no new safety signals, and demonstrated preliminary antitumor activity in pts with advanced malignancies including those with FGF/FGFR alterations. Clinical trial information: NCT02393248 .

A randomized phase II study comparing mFOLFOX-6 combined with axitinib or bevacizumab or both in patients with metastatic colorectal cancer (mCRC).

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 485-485 ◽  
Author(s):  
J. R. Infante ◽  
A. L. Cohn ◽  
T. R. Reid ◽  
W. J. Edenfield ◽  
T. Cescon ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Ii Study ◽  
Objective Response ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Antiangiogenic Agents ◽  
Open Label ◽  
Open Label Phase ◽  
C 32 ◽  
Ecog Ps

485 Background: Vascular endothelial growth factor receptor inhibitors, including axitinib (AG-013736), may be useful in treating patients with mCRC. The goals of this study were to estimate the objective response rate (ORR), progression-free survival (PFS), overall survival (OS) and safety in patients with mCRC treated with mFOLFOX-6 combined with axitinib or bevacizumab or both. Methods: Patients with mCRC untreated with any systemic chemotherapy >12 months prior to enrollment, ECOG PS 0/1, adequate organ function, and controlled hypertension were eligible for this randomized, open-label, phase II study. Patients receiving prior treatment with antiangiogenic agents or those who were pregnant were ineligible. All patients received standard mFOLFOX-6 treatment and were randomized to receive either axitinib 5 mg (Arm A), or bevacizumab 5 mg/kg (Arm B), or axitinib 5 mg + bevacizumab 2 mg/kg (Arm C). Axitinib was administered orally twice daily. Efficacy was determined by RECIST criteria. Results: A total of 42, 43, and 41 patients were enrolled in Arms A, B, and C, respectively. The ORR was 29%, 49%, and 39% for Arms A, B, and C, respectively. Median PFS was 315 days, 350 days, and 377 days, with 1-year survival of 72%, 79%, and 80% for Arms A, B, and C, respectively. Discontinuations due to adverse events (AEs) were more common in Arm A (36%), than in Arms B (19%) or C (32%). More patients withdrew from Arm A (18%) than from Arms B (5%) or C 12%). The rates of grade 3 AEs were similar across arms, except for hypertension and fatigue which were more common in Arms A (15% and 12%) and C (21% and 29%) compared with Arm B (2% and 12%). Serious AEs were reported by 41%, 40%, and 56% of patients in Arms A, B, and C, respectively; the most common were gastrointestinal disorders (21%, 16%, 15%, respectively). Conclusions: In combination with mFOLFOX-6 chemotherapy, treatment with axitinib resulted in a lower ORR but comparable survival to bevacizumab and this did not appear to improve significantly in the presence of both agents. This result may have been affected by the higher numbers of discontinuations and withdrawals in Arm A compared with the other 2 arms. [Table: see text]

Open label phase II clinical trial of orteronel (TAK-700) in metastatic or advanced non-resectable granulosa cell ovarian tumors: The Greko II study.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 5577-5577 ◽  
Author(s):  
Jesús García-Donas ◽  
Laia Garrigos ◽  
Nuria Lainez ◽  
Ana Santaballa ◽  
Andres Redondo ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Granulosa Cell ◽  
Phase Ii ◽  
Clinical Benefit ◽  
Locally Advanced ◽  
Sample Size Calculation ◽  
Open Label ◽  
Clinical Benefit Rate ◽  
Open Label Phase ◽  
The Impact

5577 Background: Granulosa-cell tumors (GCT) of the ovary are a rare entity characterized by presenting a punctual mutation at the FOXL2 gene 402C→G (C134W). Such mutation leads to a disregulation and overstimulation of the steroidogenic pathway and, ultimately, hormone overproduction. A prior trial by our group (GREKO I trial-GETHI 2011-03; NCT01584297) showed promising activity of ketoconazole, a CYP17 inhibitor used to control steroidogenesis in several conditions. Thus, we aimed to assess the activity of Orteronel (TAK700), a selective inhibitor of 17, 20-lyase, in GCT. Methods: An open-label phase II single arm clinical trial was designed for women with metastatic or locally advanced non-resectable GCT who harbored the somatic mutation FOXL2 402C→G (C134W) and who had not received prior treatment with any CYP17 inhibitor. Treatment consisted on Orteronel 300mg BID, given orally, continuously in a 28-day treatment cycle. The primary objective was clinical benefit rate; secondary objectives were response rate, progression free and overall survival, assessment of the impact of Orteronel in reducing hormonal overproduction and toxicity. Sample size calculation was based on a two stage Simon´s design. A power of 80% was set to differentiate between a 5% and a 25% clinical benefit rate. 20% of losses had been assumed thus 20 patients were scheduled to be enrolled. Results: Since 30/06/2014 to 11/01/2017 10 patients have been included in 9 participating institutions members of Spanish Group for Research in Orphan and Unfrequent Tumors (GETHI). Due to a low recrutiment rate the study was terminated early. Median PFS was 3 months 95%CI (0-12) with 3 patients achieving disease stabilization longer than 12 months. 2 patients remain on treatment after 16 and 14 months. Clinical benefit rate (CR + PR + SD) was 50%, 95%CI (19%-81%). Seven patients have progressed and 2 have died. Only 6 suspected unresected adverse reactions (SUSARs) have been communicated so far (chest pain, fever, febrile neutropenia, eosinophila, neutropenia and anemia). Conclusions: Orteronel achieved a significant clinical benefit in advanced GCT with an favorable toxicity profile. Clinical trial information: NCT02101684.

Phase II, noncomparative, open label, multicenter, study of osimertinib, in patients with locally advanced or metastatic EGFR mutated, T790M undetectable or unknown non-small cell lung cancer (Stage IIIB-IV) after no immediate prior EGFR TKI (OSIRIS study).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21116-e21116
Author(s):  
Hector J. Soto Parra ◽  
Laura Noto ◽  
Francesco Verderame ◽  
Domenico Galetta ◽  
Vito Barbieri ◽  
...  
Keyword(s):  
Phase Ii ◽  
Null Hypothesis ◽  
Type I Error ◽  
Objective Response ◽  
Locally Advanced ◽  
Local Therapy ◽  
Attrition Rate ◽  
Type I ◽  
Open Label ◽  
Egfr Tki

e21116 Background: Osimertinib (OSI) is a potent irreversible EGFR TKI approved for 1st line therapy advanced EGFR+ NSCLC and for 2nd line T790M+ pts. The AURA trial showed promising results even in pts with T790M- NSCLC after no immediate prior OSI in locally advanced or metastatic EGFR+ NSCLC, T790M undetectable or unknown, after 1st line EGFR TKI and subsequent chemotherapy. Methods: This phase II trial was performed to investigate the role OSI in locally advanced or metastatic EGFR+ NSCLC, T790M undetectable or unknown, after 1st line EGFR TKI (1 or 2 generation) and subsequent chemotherapy. Eligible pts (M or F, > 18 years, ECOG 0-2) received OSI (80 mg/day) until disease progression or unacceptable toxicity. Objective response rate (ORR) was the primary endopoint. Assuming a 10% attrition rate, 90 pts were planned to be enrolled according to the Optimal Simon’s 2 stage design. In the first stage, 32 pts were planned to be accrued, and if ≤ 3 responses were observed the study would be stopped. Otherwise, 49 additional pts were planned to be accrued. The null hypothesis would have been rejected if ≥ 12 responses were observed. This design yields a type I error rate of 0.05 and 80% power. Results: From May 2017 to October 2020, a total of 54 pts were enrolled (17 M and 37 F, mean age 66 years). The study was stopped early due to an extremely slow enrolment rate. However, the ORR of 31.5% (95% CI 19.5% - 45.5%) was significantly higher than the null hypothesis of 9% (p<0.0001). 17 pts obtained a partial response and 20 a stable disease with an overall disease control rate of 68.5%. Median PFS was 9 mos and median OS was 15 mos. Forty-one pts experienced at least 1 adverse event (51.8% treatment related), more than 90% Grade 1 or 2, the most common being diarrhea. Conclusions: Despite early termination and incomplete recruitment, the treatment with OSI in pts with undetectable or unknown T790M showed a significant ORR and a PFS in line with results in T790M+. Currently, OSI represents the preferred option in naïve pts with EGFR+ NSCLC, regardless of T790M status and for pts who progress the recommended subsequent therapies include local therapy, continuing OSI or chemotherapy; in this new scenario, our results confirm that OSI rechallenge in subsequent line after chemotherapy should be explored. This research was conducted with support from AstraZeneca. Clinical trial information: 2016-002555-17.

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