Investigator-sponsored trial of efficacy and tolerability of cabozantinib (cabo) at lower dose: A dose-finding study in men with castration-resistant prostate cancer (CRPC) and bone metastases.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 4566-4566
Author(s):  
Richard J. Lee ◽  
M. Dror Michaelson ◽  
Philip James Saylor ◽  
Carol Ann Gurski ◽  
Stephen M. Rothenberg ◽  
...  
Keyword(s):  
Bone Metastases ◽  
Dose Level ◽  
Bone Scan ◽  
Detection System ◽  
Complete Response ◽  
Treatment Interruption ◽  
Dose Finding ◽  
Castration Resistant Prostate Cancer ◽  
40Mg Daily ◽  
Level 1

4566 Background: Cabo (XL184) is an oral inhibitor of MET and VEGFR2. In a randomized discontinuation trial of cabo 100mg daily, 76% of men with CRPC and bone metastases had partial or complete resolution of bone scan lesions as early as week (wk) 6. However, treatment was limited by adverse events (AEs), with dose reductions in 51% of patients (pts), and discontinuations in 10%. The current study was designed to determine the efficacy and tolerability of cabo at lower starting doses. Methods: An adaptive response scheme was used to determine the lowest active daily cabo dose among dose levels +1 (60mg), 0 (40mg), and -1 (20mg). The primary endpoint was wk 6 bone scan response (BSR) assessed with an automated FDA 510(k) approved computer-aided detection system. A ≥30% decrease in total bone scan lesion area (BSLA) was defined as a response. The first cohort was treated at dose level 0. The number of responses (≥8 vs. <8 among 11 evaluable pts) was used to select the dose level (-1 vs. +1) for the second cohort. Based on the observed BSR rate in the second cohort of 11 pts, a dose was selected for expansion to treat 13 more pts. Results: The study completed planned enrollment of 36 pts. Median age was 66; 44% were docetaxel-pretreated. Among 12 pts enrolled at dose level 0, there were 10 BSRs at wk 6 including 1 complete response (CR), and 1 pt with stable disease (SD). The median decrease in BSLA was 62%. Ten pts evaluated at wk 12 included 9 BSRs (3 CRs), and 1 sustained SD. Among 11 pts then treated at dose level -1, 10 pts were evaluable at wk 6: 1 BSR, 5 SD, and 4 had progressive disease. No pts in the 2 cohorts required dose reduction or treatment interruption at 12 wks; 1 pt discontinued due to grade 3 AEs (anorexia, fatigue). 6/12 pts with ≥6 months follow-up remain on study. 5/5 pts enrolled at 40mg with CTCs ≥5 per 7.5mL converted to <5. Thirteen pts accrued to the expansion cohort at 40mg daily had confirmed high BSR rate. Conclusions: Cabo 40mg daily achieves a high BSR rate in men with CRPC and bone metastases, and is associated with better tolerability than previously reported for cabo 100mg daily.

Phase I trial of RAD001 (R), bevacizumab (B), and docetaxel (D) for castration-resistant prostate cancer (CRPC)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 5154-5154 ◽  
Author(s):  
M. E. Gross ◽  
J. Soscia ◽  
S. Sakowsky ◽  
O. Castellanos ◽  
D. B. Agus
Keyword(s):  
Growth Factor ◽  
Dose Level ◽  
Adaptive Design ◽  
Complete Response ◽  
Neutropenic Fever ◽  
Dose Finding ◽  
Castration Resistant Prostate Cancer ◽  
Vegf Inhibitors ◽  
Dose Modifications ◽  
Dose Levels

5154 Background: Targeting of mTOR and vascular endothelial growth factor (VEGF) alone or with chemotherapy has been reported for CRPC. We report a dose finding study combining mTOR and VEGF inhibitors along with docetaxel for advanced CRPC. Methods: Eligible patients (pts) had progressive, metastatic, chemo-naive CRPC. A modified adaptive design was used to explore 3 dose levels. 3 pts were treated in each cohort, expanded by 3 pts if a dose limiting toxicity (DLT) was observed. If no DLT occurred after all pts completed 2 cycles in a cohort, pts were enrolled at the next dose level. If a DLT was seen in 2 pts, that dose level was closed. Dose levels included: cohort 1 (D 75 mg/m2, R 2.5 mg, B 15 mg/kg); cohort 2 (D 75 mg/m2, R 5 mg, B 15 mg/kg); and cohort 3 (D 65 mg/m2, R 5 mg, B 15 mg/kg). D+B was given IV day (d) 1 and R PO days 1–21 on a 21 d cycle. Efficacy is explored as: maximal confirmed PSA decline; partial or complete response (PR+CR) by RECIST criteria; and/or changes in bone scintigraphy. Results: 12 patients have been enrolled to complete the dose-finding phase. Baseline median (range) values include: age 70 (58–78) yrs, PSA 115 (4–1336) ng/mL, alkaline phosphatase 107 (37–763) U/L. All pts had PSA elevations, 5 pts had metastasis to lung and/or lymph nodes. 9 pts had bone metastases. Common toxicities were fatigue and mucositis. DLTs by dose level is summarized as: cohort 1, DLT in 1 of 6 pts (neutropenic fever/grade (Gr) 3, pneumonia/Gr 3, 1 individual pt); cohort 2, DLT in 2 of 2 pts (neutropenic fever /Gr 3, 2 pts); cohort 3, DLT in 3 of 4 pts (neutropenic fever /Gr 3 and Gr 5, pulmonary embolism/ Gr 3, 3 pts). A pt in cohort 3 died from neutropenic fever and sepsis at cycle 3 despite dose modifications and growth factor support. Preliminary measures of efficacy by method of assessment and cohort assignment are summarized ( Table ). Conclusions: We conclude that the cohort 1 dose level of D 75 mg/m2, R 2.5 mg, B 15 mg/kg is safe and demonstrates anti-cancer efficacy. Pt accrual continues at this dose level for the dose-expansion phase of the study. [Table: see text] No significant financial relationships to disclose.

Phase I trial of metronomic cyclophosphamide (CTX) and lenalidomide (LEN) in patients with castration-resistant prostate cancer (CRPC).

2012 ◽  
Vol 30 (5_suppl) ◽  
pp. 164-164
Author(s):  
Jue Wang ◽  
Timothy R. McGuire ◽  
James K. Schwarz ◽  
Jane L Meza ◽  
James E E Talmadge
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Performance Status ◽  
Patient Characteristics ◽  
Maximum Tolerated Dose ◽  
Clinical Activity ◽  
Castration Resistant Prostate Cancer ◽  
Ecog Performance Status ◽  
Level 1 ◽  
Grade 3

164 Background: Angiogenesis and suboptimal antitumor immune response are important in the progression of CRPC. Both LEN and metronomic CTX have known anti-angiogenic and immunomodulatory activities. A phase I study of a novel combination of metronomic CTX with LEN in patients with CRPC who have failed prior docetaxel therapy was initiated to assess safety and effects on potential biomarkers. Methods: CTX was given 50 mg PO QD(day 1-28) and LEN 10-25 mg PO QD(day 1-21) on a 28 day cycle. Dose limiting toxicity was defined as any treatment-related grade 4 hematologic event or grade 3 / 4 non-hematologic event during cycles one. Quantification of circulating tumor cells (CTC), plasma cytokines, analgesic consumption and quality of life assessments were performed. Measurement of Treg and MDSCs were performed in some patients. Results: 17 patients with CRPC have been enrolled in L0-4; all patients are evaluable for toxicity. Patient characteristics include: ECOG performance status 0/1= 4/13; median age=77 (range 50–86); median PSA=36.7 (range 1.36–2287). Dose level 1 (CTX 50 mg/d, LEN 10 mg/d) was expanded to 6 patients after one out of three initial patients was removed from the study for Gr 3 gastrointestinal bleeding (in cycle 1). Dose level 1 (CTX 25 mg/d, LEN 10 mg/d) had no DLT’s. The maximum tolerated dose has not yet been reached. Other Grade 3/4 toxicities observed after cycle 1 included grade 3 pain (N=1), grade 3 neutropenia (N=4), grade 3 thrombocytopenia (N=2), grade 4 neutropenia (N=2). Most frequent grade 1 and 2 toxicities included anemia, fatigue, neutropenia, and hypocalcemia. Overall, 9 of 14 patients (64%) have experienced a reduction in PSA. One patient had partial response after one cycle. Stable disease was documented in 5 of 14 (36%) evaluable patients. Two inflammatory cytokines, IL-6 (N = 19; r = 0.64; p = 0.0035) and IL-8 (N = 9; r = 0.86; p = 0.0028), were found to significantly correlated with PSA. Conclusions: The combination of metronomic CTX and LEN can be safely administered. Preliminary clinical activity was observed in this heavily-pretreated patient population. Enrollment to this study continues and clinical and biomarker studies are ongoing.

A phase I dose-finding study of everolimus in combination with capecitabine and oxaliplatin (XELOX) as the first-line chemotherapy for patients with advanced gastric cancer.

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 86-86
Author(s):  
Inkeun Park ◽  
Min-Hee Ryu ◽  
Baek-Yeol Ryoo ◽  
Myoung Joo Kang ◽  
Changsuk Lee ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Phase I ◽  
Advanced Gastric Cancer ◽  
Dose Level ◽  
Dose Intensity ◽  
Dose Finding ◽  
Good Tolerability ◽  
Level 1 ◽  
Dose Levels ◽  
Line Chemotherapy

86 Background: The purpose of this phase I study is to determine the recommended dose (RD) of everolimus (E), an mTOR inhibitor, in combination with capecitabine (XEL) and oxaliplatin (OX) and to explore feasibility of EXELOX at the RD in advanced gastric cancer (AGC). Methods: The standard 3+3 method was used to determine the RD of 3-weekly EXELOX during the first cycle. The doses of each drug [E (mg/day, D1-D21)/XEL (mg/m2/day, D1-D14)/OX (mg/m2, D1)] were as follows: level 1, 7.5/1600/100; level 2A, 7.5/1,600/130; level 2B, 7.5/2,000/100; level 3A, 10/1,600/130; level 3B, 10/2,000/100; level 4, 7.5/2,000/130. Results: During the first cycle of chemotherapy, no dose limiting toxicity (DLT) was noted in each cohort of 3 patients (pts) at dose levels 1-3A. At dose level 3B, 1 DLT (delay of the next cycle over 3 weeks because of Gr2 thrombocytopenia and Gr2 AST) was observed out of 6 pts. At dose level 4, DLTs (Gr3 fatigue and Gr4 thrombocytopenia) were found in 2 out of 3 pts. However, with frequent dose delay or reduction in subsequent cycles, the actual dose intensity of XELOX during the first 3 cycles was not higher at dose levels 2 or 3 than at dose level 1. Accordingly, dose level 1 was finally considered more suitable to maintain the actual dose intensity over chemotherapy cycles. At dose level 1, with no DLT during the first 3 cycles in 3 more pts accrued to confirm the safety, 12 additional pts were enrolled in the extension cohort to explore feasibility of EXELOX in the aspect of efficacy. Among 16 patients with measurable disease at dose level 1, 8 (50%) pts achieved a confirmed PR, 7 (44%) had SD, and 1 (6%) showed PD as a best response. With a median follow-up period of 12 months (range 4.9–12.8 months), the median progression-free survival and overall survival were 5.5 and 8.1 months, respectively at dose level 1. Conclusions: In this study, the doses of XEL (1,600 mg/m2/day), OX (100 mg/m2), and E (7.5 mg/day) were recommended with good tolerability for the 3 weekly EXELOX combination as the 1st line chemotherapy for AGC. The efficacy of this combination needs to be evaluated in future trials. Clinical trial information: NCT01049620.

Evaluation of bone metastasis of castration-resistant prostate cancer after enzalutamide and abiraterone using Bone Scan Index on bone scintigraphy.

2017 ◽  
Vol 35 (6_suppl) ◽  
pp. e596-e596
Author(s):  
Suguru Kadomoto ◽  
Kouji Izumi ◽  
Takahiro Nohara ◽  
Konaka Hiroyuki ◽  
Yoshifumi Kadono ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Bone Metastasis ◽  
Bone Metastases ◽  
Bone Scintigraphy ◽  
Bone Scan ◽  
Average Rate ◽  
Castration Resistant Prostate Cancer ◽  
Bone Scan Index ◽  
Castration Resistant ◽  
Better Than

e596 Background: It was ambiguous till now to evaluate the change of bone metastasis by various treatments. To quantify the change of bone metastases by enzalutamide, abiraterone, and docetaxel for the castration-resistant prostate cancer (CRPC) with bone metastases (bmCRPC), we employed Bone Scan Index (BSI) on bone scintigraphy. Methods: We retrospectively evaluated the change of PSA and bone metastases of CRPC patients who were treated with enzalutamide (Enz), abiraterone (Abi) and/or docetaxel (DOC) in our hospital. All patients underwent Tc-99m MDP bone scintigraphy. The degree of bone metastases was analyzed using BSI, which was calculated by BONENAVI (FUJIFILM RI Pharma, Japan; EXINIbone, EXINI Diagnostics, Sweden). 19 patients were treated with enzalutamide (8 cases: pre-docetaxel, 11 cases: post-docetaxel). The median PSA of patients treated with Enz was 12.64 ng/ml (1.63-199 ng/ml). And 11 patients were treated with abiraterone (5 cases: pre-docetaxel, 6 cases: post-docetaxel). The median PSA of patients treated with Abi was 26.37 ng/ml (2.29-199 ng/ml). Results: We observed decline of PSA in 18/30 cases (9 cases: pre-DOC, 9 cases: post-DOC). Decline of PSA to 50% or more was observed in 14 cases. In contrast, decline of BSI was observed in 53.3% (16/30) cases and decline of PSA to 25% or more was observed in only 6 cases. BSI decreased in 84.6% (11/13) of pre-DOC setting and in 29.4% (5/17) of post-DOC setting indicating that change of BSI was poor in post-DOC setting. However, DOC had already decreased BSI in 91.7% (11/12) before Abi or Enz treatment. Moreover, the average rate of BSI decline in the patients that BSI decreased by DOC was better than the patients that BSI decreased by Abi/Enz (-48.46% vs -28.56%). Finally, although the rate of BSI change by Enz was weakly correlated with the rate of PSA decline (y = 0.3906x + 25.35, R2 = 0.3423), BSI continued to increase in four cases in spite of PSA decline. Conclusions: BSI using BONENAVI on bone scintigraphy was helpful for evaluating the effectiveness of treatment and following-up of bmCRPC.

Phase I dose-finding study of sorafenib in combination with capecitabine and cisplatin as a first-line treatment in patients with advanced gastric cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 4559-4559
Author(s):  
C. Kim ◽  
J. Lee ◽  
Y. Choi ◽  
B. Kang ◽  
M. Ryu ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Phase I ◽  
Dose Level ◽  
Dose Finding ◽  
Finding Study ◽  
Level 3 ◽  
Dose Finding Study ◽  
Level 1 ◽  
Grade 3 ◽  
Level 2

4559 Background: We conducted a phase I dose-finding study of sorafenib (S) in combination with capecitabine (X) and cisplatin (P) in patients with previously untreated metastatic or inoperable advanced gastric cancer. Methods: Four dose levels of S, X, and P combination were tested. The doses of S (p.o. daily), X (p.o. on days 1–14), and P (i.v. on day 1) were escalated at the following schedule; level 1: S 400 mg/d, X 1,600 mg/m2/d, P 80 mg/m2; level 2: S 800 mg/d, X 1,600 mg/m2/d, P 80 mg/m2; level 3: S 800 mg/d, X 2,000 mg/m2/d, P 80 mg/m2; level 1A: S 800 mg/d, X 1,600 mg/m2/d, P 60 mg/m2. The cycle was repeated every 3 weeks. Dose limiting toxicities (DLTs) were evaluated only in the first cycles and a standard 3+3 dose escalation design was implemented. Results: A total 21 pts were enrolled in the study. No DLTs were observed at dose level 1 (n=3). One DLT (grade 3 diarrhea) was noted at dose level 2 (n=6), and 2 DLTs (two grade 4 neutropenias longer than 5 days in duration) were observed at dose level 3 (n=6), which made the level 3 dose the maximum tolerated dose (MTD). However, at cycle 2 and thereafter at dose level 2, the relative dose intensity (RDI) of S and X could not be maintained (mostly below 80%) due to the frequent dose reductions and cycle delays. So, we explored a new dose level (1A) between dose level 1 and 2. Since no DLTs were found in 6 patients at level 1A with RDI mostly above 80% throughout the treatment period, level 1A was determined as recommended dose (RD). Most frequent grade 3 and 4 hematologic toxicities were neutropenia (25.0% of cycles), and most frequent grade 2 and 3 non-hematologic toxicities were hand-foot syndrome (9.4%), asthenia (7.0%), and anorexia (5.5%). The objective responses were confirmed in 10 out of 16 patients with measurable lesions (62.5%; 95% CI, 38.8–86.2%). With a median follow-up of 8.1 months, estimated median progression-free survival was 10.0 months (95% CI, 1.6–18.4 months) and median overall survival has not been reached. Conclusions: Diarrhea and neutropenia were DLTs in this S, X, and P combination. The dose schedule of sorafenib 400 mg po bid daily with capecitabine 800 mg/m2 po bid on days 1–14, and cisplatin 60 mg/m2 iv on day 1 in every 3 weeks is recommended for further development in AGC. [Table: see text]

EORTC 24051: Unexpected side effects of a phase I study of TPF induction chemotherapy (IC) followed by chemoradiation (CRT) with lapatinib (LAP), a dual EGFR/ErbB2 inhibitor, in patients with locally advanced larynx and hypopharynx squamous cell carcinoma (LA-LxHxSCC)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 6017-6017
Author(s):  
P. M. Specenier ◽  
Y. Lalami ◽  
J. Vermorken ◽  
D. Lacombe ◽  
I. El-Hariry ◽  
...  
Keyword(s):  
Dose Level ◽  
Renal Toxicity ◽  
Locally Advanced ◽  
Treatment Interruption ◽  
Safety Issues ◽  
Male Patients ◽  
Level 1 ◽  
Grade 3

6017 Background: CRT is considered a standard approach for LA-LxHxSCC. TPF IC regimen seems to improve outcome in locally advanced head and neck SCC. The addition of LAP was investigated in combination with a sequential therapeutic approach (IC→ CRT). Methods: Eligible tumors were SCCHN: T3-T4 larynx (Lx), T2-T4 hypopharynx (Hx) N0–3 M0. The objective of this trial is to determine MTD, DLT and recommended dose of LAP when administered with TPF IC (docetaxel (T) 75mg/m2 (60 mg/m2 for the first cycle) d1, CDDP 75mg/m2 d1, 5FU 750mg/m2/d continuous infusion d1-d5 q3weeks) followed by CRT (weekly carboplatin AUC 1.5 and RT 70Gy in 7 weeks; 2Gy/fx). LAP is administered concomitantly with IC (escalating dose 500–1500mg po daily) and during CRT (1,500 mg daily). Results: Seven male patients were included; tumor sites: LX (n = 3) / Hx: (n = 4), median age 59 years (range: 47–79), WHO PS 0–1, no severe or uncontrolled comorbidity. Three pts were included in the first cohort, at dose level 1 (LAP 500 mg daily plus TPF IC). Renal toxicity was observed among these 3 pts (grade 4 [n = 1], grade 2 [n=1] and grade 1 [n=1]), with 1 DLT, leading to treatment interruption in this group. This nephrotoxicity was reversible after stopping lapatinib and hydration of the patients. As LAP plus cisplatinum plus RT was feasible in another study, a second cohort was conducted in 4 pts, receiving LAP at the same dosage, and docetaxel (T) was only introduced from cycle 2 of IC to see what is the role of T in the observed side effect. Two DLTs were observed among this second cohort of subjects: one pt presented a grade 2 renal toxicity, grade 3 diarrhea and dehydration and a second pt presented a grade 3 anorexia and grade 3 stomatitis. Based on the occurrence of 3 DLTs at the first dose level of LAP, patient recruitment was closed. Despite these safety issues, all patients recovered and were treated off-study. They will receive follow-up as foreseen by the protocol. Conclusions: These data suggest that LAP should not be combined with TPF IC regimen for LA-LxHxSCC due to prohibited toxicity. [Table: see text]

Phase I/II study of neoadjuvant carboplatin, eribulin mesylate, and trastuzumab (ECH) for operable HER2 positive (HER2+) breast cancer.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. TPS659-TPS659
Author(s):  
Lee Steven Schwartzberg ◽  
Kurt W. Tauer ◽  
Robert C. Hermann ◽  
Petros G. Nikolinakos ◽  
Arthur C. Houts
Keyword(s):  
Breast Cancer ◽  
Phase I ◽  
Dose Level ◽  
Phase Ii ◽  
Primary Endpoint ◽  
Pathologic Complete Response ◽  
Complete Response ◽  
Eribulin Mesylate ◽  
Her2 Breast Cancer ◽  
Level 1

TPS659 Background: Carboplatin, docetaxel and trastuzumab (TCH) regimen yields substantial pathologic complete response (pCR) in operable HER2+ breast cancer. Eribulin mesylate (E) is a tubulin inhibitor recently shown to improve overall survival compared to taxanes and other agents in heavily pretreated metastatic breast cancer patients. This trial was designed to determine the maximum tolerated dose (MTD) of E in combination with CH (Phase I) and to determine efficacy and safety of the ECH regimen (Phase II) given as neoadjuvant therapy to early stage HER2+ breast cancer with pathologic complete response the primary endpoint. Methods: This is a multicenter prospective open label single arm trial. Eligible patients were operable stage IIA – IIIB HER2+ breast cancer, ECOG 0-1, normal LVEF, QTc < 480 msec, < grade 1 neuropathy and no history of invasive cancer within the past 3 years. Phase I planned up to 12 patients from 4 centers to 1 of 3 E dose cohorts, with pts treated at the MTD also evaluable for Phase II. Starting dose level 0 was 1.1 mg/m2 with escalation to dose level +1 at 1.4 mg/m2 and de-escalation to dose level -1 at 0.9 mg/m2 if necessary. ECH was given IV for six 3-week cycles with E d1 and d8; C AUC 6 d1; and H 8 mg/kg loading dose d1C1 and 6 mg/kg d1C2-C6. H is scheduled to continue after surgery to complete 1 year of treatment. C1 dose limiting toxicities (DLTs) were defined as: grade 4 thrombocytopenia, anemia, or neutropenia lasting > 5 days; any grade 3-4 non-hematologic toxicity attributable to E, C, H, or the combination; inability to deliver all three agents at assigned dose and schedule. Standard 3+3 dose escalation design was used. At present, 6 patients have been enrolled at dose 0 and 6 have been enrolled at dose +1. The MTD for E has not yet been determined. Phase II has planned enrollment of 44 additional patients from 8 centers with primary endpoint rate of pCR at surgery to be performed 4-8 weeks after completion of ECH and secondary endpoints of safety to include peripheral neuropathy and cardiac toxicity at treatment completion and 1 year follow up. Clinical trial information: NCT101388647.

A phase Ib study of second-line therapy with panitumumab, irinotecan, and everolimus (PIE) in metastatic colorectal cancer (mCRC) with KRAS wild type (WT).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e14506-e14506 ◽  
Author(s):  
Amanda Rose Townsend ◽  
Louise Pirc ◽  
Pamela Cooper ◽  
Niall C. Tebbutt ◽  
Christos Stelios Karapetis ◽  
...  
Keyword(s):  
Dose Level ◽  
Mammalian Target Of Rapamycin ◽  
Maximum Tolerated Dose ◽  
Dose Finding ◽  
Treatment Delays ◽  
Phase Ib ◽  
Combination Methods ◽  
Level 1 ◽  
Grade 3 ◽  
Level 2

e14506 Background: The mammalian target of rapamycin (mTOR) is a key downstream protein activated via PI3K-AKT pathway, and regulates cell growth, proliferation, and survival. Inhibition of mTOR in addition to EGFR may overcome upstream resistance to EGFR inhibitors in CRC. This is a phase Ib study to determine the maximum tolerated dose (MTD) of the PIE combination. Methods: Patients with KRAS WT mCRC following failure of first line fluoropyrimidine based therapy received IV irinotecan and panitumumab every 2 weeks, and everolimus orally throughout a 14 day cycle. Dose finding used a standard 3+3 design with the MTD defined as the dose with dose limiting toxicity (DLT) in ≤1/6 patients. A DLT is any of the following in the first 28 days; febrile neutropenia, G3/G4 neutropenia > 14 days, any G4 thrombocytopenia, any non-haematologic event of G4 or of G3 for >7 days, treatment delays of >14 days. Dose level 1; irinotecan 200mg/m2, panitumumab 6mg/kg, everolimus 5mg alternate days. Dose level 2; irinotecan 200mg/m2, panitumumab 6mg/kg, and everolimus 5mg daily. Results: 15 patients have been enrolled into the study, 2 withdrew prior to receiving any therapy. Five patients were enrolled at dose level 1. Two patients were not evaluable. Of the three evaluable patients there was no DLT. Three patients were then treated at dose level 2. Following one DLT (grade 3 mucositis >7 days), the cohort was expanded to 5 evaluable patients but suspended after a further DLT (grade 3 mucositis > 7 days). Other grade 3 toxicities were anorexia, rash, vomiting, and hypersensitivity. There were no grade 4 toxicities. Dose level 1 was expanded by 3, to a total of 6 evaluable patients. Grade 3 toxicities were mucositis (17%), fatigue (17%), diarrhoea (33%), rash (17%), hypomagnesemia (17%), and neutropenia (17%). There was no DLT. Conclusions: Dose level 2 exceeded the MTD. Dose level 1 appears tolerable and warrants further investigation. The phase II component of the study is ongoing. Clinical trial information: NCT01139138.

Pilot trial of ibrutinib plus nivolumab in patients (pts) with metastatic renal cell cancer (mRCC): Results from a dose-finding cohort.

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 600-600 ◽  
Author(s):  
Primo Lara ◽  
Mamta Parikh ◽  
Daniel Robles ◽  
Frances Lara ◽  
Frederick J. Meyers ◽  
...  
Keyword(s):  
Dose Level ◽  
Cell Cancer ◽  
Pilot Trial ◽  
Suppressor Cells ◽  
Initial Response ◽  
Patient Characteristics ◽  
Dose Finding ◽  
Histologic Subtype ◽  
Once Daily ◽  
Level 1

600 Background: Immune checkpoint inhibitor therapy (CPI) has transformed the management of pts with mRCC, with a fraction experiencing durable tumor responses. However, most eventually develop disease progression after either an initial response to CPI or while on CPI. Newer agents that modulate immune response can possibly potentiate CPI therapy. The ITK/ETK/BTK inhibitor ibrutinib has been reported to inhibit myeloid derived suppressor cells in preclinical models and to potentiate CPI. We conducted an investigator-initiated pilot trial of ibrutinib plus the PD1 inhibitor nivolumab in mRCC pts, particularly in those previously exposed to CPI. Here we report initial safety and efficacy results from the dose-finding cohort. Methods: Pts with mRCC of any histologic subtype and who have completed at least one line of prior systemic therapy including prior CPI were eligible. Pts must have acceptable end-organ function and Zubrod PS of 0-2. Treatment consisted of nivolumab 240 mg IV q2 weeks plus ibrutinib 560 mg (dose level 0) or 420 mg (dose level -1) orally once daily. Cycle length was 28 days. Dose limiting toxicity (DLT) was defined as any Grade(Gr) 3+ adverse event (AE) attributable to therapy. Results: As of 9/18/17, 12 pts have been enrolled, six to each dose level. Patient characteristics: Mean age = 62 years (range 44-78); Male sex = 7 (58%); White race = 9 (75%); Prior CPI = 11 (92%). Three pts experienced one DLT each in dose level 0 (all Gr3): elevated lipase, hypoalbuminemia, & nausea. Only 1 DLT has been seen thus far in dose level -1 (Gr3 infection). The most common Gr3+ AEs include anemia (n = 5), ALT elevation (4), AST elevation (3), nausea (3), hypoalbuminemia (2), esophagitis, infection, lipase increase, and vomiting (1 each). Two pts with prior CPI had partial tumor response (1 confirmed, 1 unconfirmed). Conclusions: Ibrutinib at a dose of 420mg orally once daily in combination with nivolumab 240mg IV q 2 weeks appears feasible and tolerable in mRCC patients. No unique immune-related AEs have been seen thus far. Anti-tumor activity was seen in 2 pts previously exposed to PD1-targeted therapy. Further evaluation of this combination is warranted. (Supported by Pharmacyclics and UCDCCC). Clinical trial information: NCT02899078.

A phase II, open-label, multi-arm study of TAS-115 for castration-resistant prostate cancer patients with bone metastases.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 164-164
Author(s):  
Hiroji Uemura ◽  
Nobuaki Matsubara ◽  
Hirotsugu Uemura ◽  
Satoshi Nagamori ◽  
Hiroyoshi Suzuki ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Bone Metastases ◽  
Bone Scan ◽  
Response Rate ◽  
Short Form ◽  
Phase 2 ◽  
Castration Resistant Prostate Cancer ◽  
Open Label ◽  
Castration Resistant ◽  
Anti Tumor Activity

164 Background: TAS-115, a novel multi-kinase (eg, MET, VEGFR) inhibitor has also shown to inhibits Feline McDonough Sarcoma oncogene (FMS) kinase, Anti-tumor activity against bone metastases was observed in the preclinical and phase1 study. In this phase 2 study, the efficacy and safety of TAS-115 were evaluated in castration-resistant prostate cancer (CRPC) patients (pts) with bone metastases. Methods: This was a phase 2, open-label, multi-arm study for CRPC pts with bone metastases to evaluate the clinical anti-tumor activity of TAS-115. Pts who had visceral metastases were ineligible for this study. TAS-115 was given orally, once daily, and schedule of 5 days on/2 days off each week was repeated. This study had 2 cohorts (A and B). In cohort A, TAS-115 ranging from 200 to 400 mg/day with abiraterone acetate was given to pts prior to docetaxel. In cohort B, CRPC pts who had symptomatic bone metastases, post or unfit to docetaxel, were randomized in a 1:1 to 400 or 600 mg/day of TAS-115. The primary endpoint was bone scan index (BSI) response rate at week 12, defined as ≥ 30% decrease of BSI from baseline. BSI is a quantitative assessment of bone scan data calculated by software (BONE NAVI). Results: From Nov 2016 to Jul 2018, a total of 50 pts received TAS-115 (24 pts in cohort A and 26 pts in cohort B). BSI response rate at week 12 and best BSI response was 20.8 % and 37.5% in cohort A, and 15.4 % and 19.2% in cohort B, respectively. Any reduction of BSI was observed in 70.8% of cohort A and 61.5% of cohort B. In cohort B, pain was assessed using the Brief Pain Inventory short form and improvement was observed in 61.5% of pts. Furthermore, the reduction of bone-turnover marker (BAP, P1NP, NTx and TRACP-5b) were observed in both cohorts, but not PSA response. The major (≥ 10%) Grade 3/4 treatment-related adverse drug reactions were hypophosphataemia (21%) in cohort A, and anemia (23%), hypophosphataemia (12%) and neutrophil count decreased (12%) in cohort B. Conclusions: Preliminary anti-tumor activity to bone lesion and improved pain were observed in CRPC pts with bone metastases, and safety of TAS-115 was acceptable. TAS-115 could be a novel therapeutic agent with a favorable safety profile for CRPC with bone metastases. Clinical trial information: JapicCTI-163448.

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