Effect of sorafenib on chemotherapy resistance and refractoriness in castration-resistant prostate cancer (CRPC)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e16105-e16105
Author(s):  
C. Nabhan ◽  
K. Tolzien ◽  
T. M. Lestingi ◽  
A. Galvez ◽  
J. D. Bitran
Keyword(s):  
Clinical Benefit ◽  
Kinase Inhibitor ◽  
Chemotherapy Resistance ◽  
Complete Response ◽  
Median Number ◽  
Castration Resistant Prostate Cancer ◽  
Chemotherapy Agent ◽  
Hand Foot Syndrome ◽  
Psa Response ◽  
Grade 3

e16105 Background: There is no standard for CRPC once chemotherapy fails. In studies employing docetaxel (D), 35–39% of pts did not complete therapy due to progression and only 45–50% had a PSA response. This implies that many pts develop resistance to D. Sorafenib is a multi kinase inhibitor with antiangiogenesis properties. We hypothesized that sorafenib could overcome chemotherapy resistance in these pts. Methods: Eligible pts must have progressed while on either D or mitoxantrone (M). They received sorafenib at 400 mg orally twice/daily in addition to the chemotherapy agent they were on. Sorefinib/chemotherapy combination was given for a maximum of 6 cycles followed by sorafenib monotherapy until progression. Primary end point was safety of the sorafenib/chemotherapy combination. Secondary end points included the overall clinical benefit calculated as the sum of complete response (CR), partial response (PR), and stable disease (SD), toxicity, and time to disease progression (TTP). Results: To date, 15 pts have been enrolled; 14 are evaluable. Eleven pts were on D and 4 on M. Median age was 68 (range 61–83), median PSA was 111.2 ng/ml (13.6–1703.9). Nine pts (60%) had visceral and bone disease. Median PSA-DT pre-study was 2 months (0.5–6) and median time from last chemotherapy to starting study was 4 weeks. Median number of given cycles was 6.5 (2–12). Six pts did not require dose reduction, 2 others were re-escalated to the full dose. Sorafenib was safely combined with chemotherapy with 6 pts experiencing grade 3 fatigue, 3 developing grade 3 hand/foot syndrome, and 1 experiening grade 3 diarrhea. Eleven pts (73%) had SD radiographically that lasted a median of 6.7 months. In all, 6 out of 14 pts (42%) had a PSA decline after adding sorafenib and 3 (21%) had stable PSA. Of these 9 pts (PR+SD), 2 never doubled their PSA. Two pts had PSA decline after withdrawing sorafenib. Median TTP for PSA was 3.75 months. PSA responses did not correlate with radiographic changes or clinical benefit. With a median follow-up of 8 months, 5 pts (33%) remain alive with 1 continuing on therapy without progression. Conclusions: Sorafenib overcomes chemotherapy-refractoriness and failures in CRPC. [Table: see text]

Overcoming chemotherapy resistance in patients (pts) with chemotherapy-failure, castration-resistant prostate cancer (CRPC) with sorafenib.

2012 ◽  
Vol 30 (5_suppl) ◽  
pp. 127-127 ◽  
Author(s):  
Chadi Nabhan ◽  
Peter Hubert Cygan ◽  
Andrew Meyer ◽  
Kathy Tolzien ◽  
Angel G. Galvez ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Chemotherapy Resistance ◽  
Median Number ◽  
Castration Resistant Prostate Cancer ◽  
Chemotherapy Agent ◽  
Castration Resistant ◽  
Hand Foot Syndrome ◽  
Grade 3 ◽  
Number Of Treatment

127 Background: SOR is an oral multi kinase inhibitor that promotes apoptosis through downstream pathways that can be deregulated in CRPC leading to chemotherapy resistance. We hypothesized that SOR Could overcome chemotherapy resistance in non-responders or in those who progress shortly after stopping chemotherapy. Methods: Eligible pts were those who progressed while receiving chemotherapy [docetaxel (D) or mitoxantrone (M)] or within 12 weeks from stopping it. Pts were then continued or resumed on their last chemotherapy with the addition of SOR at 400 mg PO BID. Pts were allowed a maximum of 6 cycles of chemotherapy +SOR followed by SOR as monotherapy until progression. Primary end point: Safety of SOR+ chemotherapy. Secondary end points: Toxicity, time to progression (TTP). And responses (biochemical and radiographic) Results: Twenty-two pts were enrolled; 21 evaluable (73% Gleason ≥ 7). Median age was 68 (59-83). Median PSA was 142 ng/dl (13.6-9,584). Median time from last chemotherapy to SOR was 4 weeks. Visceral and bone disease was present in 64%. D was given in 16 pts while M in 6. Ten pts (45%) showed biochemical response (18% with >50% PSA decline). Despite progression before being on study, 16 pts (76%) achieved SD after starting SOR for a median duration of 6 months (4-12). The combination of SOR with either chemotherapy agent proved safe. Main grade 3/4 non-hematologic toxicities: Fatigue 7 (32%), 4 (18%) hand/foot syndrome, hypocalcemia and hyperglycemia in 2 pts (9%) each. Grade 3/4 leukopenia was seen in 7 (31%), neutropenia in 6 (27%), and thrombocytopenia in 2 (9%). Dose reduction of SOR occurred at least once in 15 pts (68%). Major reasons are hand/foot syndrome (22%), fatigue (22%), rash (13%), and neutropenia (9%). With a median follow-up of 19 months (3-46), 5 pts (23%) remain alive for a median OS of 8 months. TTP by PSA was 3 months (2-6) and TTP by imaging and/or clinically was 6 months (2-12). Median number of treatment cycles given was 6 (1-10). Conclusions: SOR can safely be combined with chemotherapy. SOR overcomes chemotherapy-resistance and shows biochemical and radiographic stability in this refractory pt population.

Effect of lenalidomide (LEN) on biochemical responses and clinical benefit (CB) as a single agent in chemotherapy-naive castration-resistant prostate cancer (CRPC).

2012 ◽  
Vol 30 (5_suppl) ◽  
pp. 128-128 ◽  
Author(s):  
Chadi Nabhan ◽  
Anand Patel ◽  
Dana Villines ◽  
Kathy Tolzien ◽  
Susan K. Kelby ◽  
...  
Keyword(s):  
Adverse Events ◽  
Clinical Benefit ◽  
Single Agent ◽  
Complete Response ◽  
Median Number ◽  
Castration Resistant Prostate Cancer ◽  
Serious Adverse Events ◽  
Biochemical Responses ◽  
Grade 3 ◽  
Dose Reductions

128 Background: LEN has anti-angiogenesis and immunomodulatory properties making it ideal to investigate in CRPC. We report on a phase II study investigating LEN in chemotherapy-naïve CRPC patients (pts) Methods: Eligible pts received LEN at 25 mg daily on days 1 – 21 every 28-days until progression. Daily aspirin or coumadin were required. Responses were assessed every 2 cycles. Toxicity was assessed every cycle. Primary end point: The CB of LEN [Sum of complete response (CR), partial response (PR) and stable disease (SD)]. Secondary end points: Toxicity, time to radiographic and PSA progression (TTP and TTP-PSA), time to next treatment (TTNT), overall survival (OS), and LEN’s impact on quality of life (QOL). Results: 31 pts were enrolled; 27 response-evaluable (1 withdrew consent, 3 off per choice after adverse events). Median age is 74 (range 58-89) with 24 (77%) having Gleason ≥ 7 disease. Median PSA is 66 (2.1-918.6). Six pts (19%) had liver/lung involvement. Fourteen pts (51%) showed biochemical response with 4 (15%) having >50% PSA drop. TTP-PSA is 4 months (2-11). No radiographic responses seen but 17 pts had SD for a median of 4 months (2-16) (CB=55%). Median number of LEN cycles was 3 (2-15). With a median follow-up of 18 months (5-38), 17 patients (55%) remain alive; median OS of 18 months. Grade 3/4 hematologic toxicities were most common (neutropenia 41%, leukopenia 12%, anemia 9%, thrombocytopenia 9%). Other grade 3/4 toxicities: venothromboembolism, atrial fibrillation, and dehydration (6% each). Serious adverse events (SAEs) were witnessed in 10 pts (32%) with only 1 (3%, rash) definitely related to LEN. Others were not related or possibly related. Of 27 pts, 7 (26%) had a dose reduction and 2 (7%) required two dose reductions. Dose reductions occurred after cycle 3. QOL scales suggested no adverse impact. Median TTNT is 2 months (9 pts received chemotherapy, 10 pts went onto studies, 3 pts received hormonal therapies, 4 pts received radiation, 3 pts had no therapy yet, and 2 pts remain on LEN). Conclusions: LEN is active as monotherapy in CRPC. Biochemical responses are witnessed and clinical benefit is observed. Myelosuppression is the most common toxicity.

Phase II study of sorafenib and docetaxel in men with metastatic castration resistant prostate cancer (mCRPC)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e16055-e16055
Author(s):  
J. P. Cetnar ◽  
M. A. Rosen ◽  
D. J. Vaughn ◽  
N. B. Haas ◽  
A. B. Troxel ◽  
...  
Keyword(s):  
Phase Ii ◽  
Response Rate ◽  
Kinase Inhibitor ◽  
Bone Lesions ◽  
Complete Disappearance ◽  
Castration Resistant Prostate Cancer ◽  
Dce Mri ◽  
Hand Foot Syndrome ◽  
Psa Response ◽  
Grade 3

e16055 Background: Previous trials of the antiangiogenic kinase inhibitor sorafenib in mCRPC have reported PSA elevation accompanying radiographic response, and evidence that sorafenib may potentiate docetaxel (dxl) myelosuppression. To assess the safety, antivascular effects, and activity of sorafenib and dxl in mCRPC, a phase II trial with dynamic contrast enhanced-magnetic resonance imaging (DCE-MRI) was conducted. Methods: Eligible men had mCRPC and no prior chemotherapy. Treatment consisted of dxl 75 mg/m2(day 1) and sorafenib (days 2–19) of a 21 day cycle. Patients received 7 days of sorafenib before cycle 1. Six patients received sorafenib 200mg BID and remaining patients received sorafenib 400 mg BID if <4/6 patients had grade 4 neutropenia. DCE-MRI was performed at baseline, days 8 and 28. The primary endpoint was PSA response rate (>50% PSA decline). Secondary endpoints were vascular response rate (>20% decline in area under the gadolinium curve [AUC60]), toxicity rates, and time to progression (TTP). PSA-only progression (2 consecutive PSA rises) was confirmed by a third PSA rise or radiographic progression after a 21-day drug holiday. Sample size of 69 patients in 1 stage was designed to maximize detection of significant correlations between DCE-MRI and clinical outcomes. Results: Six of 13 enrolled patients (46%) had a PSA response. A median PSA increase of 37% was observed in 73% of patients after 1 week of sorafenib. The median TTP was 8+ months. Two patients had complete disappearance of bone lesions. Grade 3 adverse events were neutropenia (77%), hand-foot syndrome (23%), anemia (15%), nausea (8%), and rash (8%). A median AUC60 decline of 40% from baseline was observed after 7 days of sorafenib, and only a 6% decline on day 28 during a scheduled sorafenib holiday. Conclusions: Sorafenib 400 mg po bid and dxl 75 mg/m2 are tolerable in men with mCRPC. Elevated PSA values in men treated with sorafenib and dxl does not always reflect disease progression. DCE-MRI can capture sorafenib's impairment of tumor vasculature in osseous metastases and rebound angiogenesis during drug holidays. Bone responses and TTP data provide evidence of encouraging activity. No significant financial relationships to disclose.

Maintenance GM-CSF in patients with castration-resistant prostate cancer (CRPC) who maximized their response to chemotherapy

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e16155-e16155
Author(s):  
J. D. Bitran ◽  
K. Tolzien ◽  
T. M. Lestingi ◽  
C. Nabhan
Keyword(s):  
Clinical Benefit ◽  
Response Duration ◽  
Complete Response ◽  
Median Number ◽  
Castration Resistant Prostate Cancer ◽  
Median Response ◽  
Gm Csf ◽  
Castration Resistant ◽  
Response To Chemotherapy ◽  
Grade 3

e16155 Background: There is no standard treatment for CRPC patients (pts) who completed chemotherapy. Time to progression (TTP) ranges from 3–6 months after stopping chemotherapy. GM-CSF (GM) is an immune-based growth factor with reported activity in CRPC. We hypothesized that GM maintenance in pts who have maximized their response to chemotherapy could delay TTP or time to next treatment (TNT). Methods: Eligible pts were those with CRPC who completed 10–12 cycles of docetaxel (D) or mitoxantrone (M) chemotherapy without progression; or those who maximized their response to chemotherapy before completing 10–12 cycles. Maximum response was defined as a <10% change in PSA repeated on two occasions with stable disease (SD) radiographically. Enrolled pts received GM at 250 ug/m2 subcutaneously for 14 days followed by 14-days of rest. GM was continued until disease progression. Primary end point was the clinical benefit defined as the sum of partial response (PR), complete response (CR) and SD. Secondary end points included toxicity, TTP, and TNT. Results: To date, 12 pts out of planned 20 have been enrolled (9 were on D and 3 on M). Median age was 78 (66–96). Median PSA at enrollment was 56.5 (0.1–566). Only 1 pt had a Gleason score < 7. Median time from initial diagnosis to GM was 70 months. Median number of chemotherapy cycles prior to GM was 9 (6–12). Eight pts (66%) had visceral and bone disease. GM was well-tolerated with no drug-related grade 3 and/or 4 toxicities. Ten pts are evaluable (1 pt withdrew consent and another did not comply). Median GM cycles received so far was 3 (2–11). With a median follow up of 11 months (2–17), 3 pts demonstrated SD and 2 had PR for an overall clinical benefit of 50%. One pt remains on study at 7 months while the median response duration for the other 4 responding pts was 7 months. Four pts never received another treatment but the median TNT in other evaluable pts was 3 months. Conclusions: GM is safe, well tolerated, and has activity in CRPC after stopping chemotherapy. Combining chemotherapy with GM should be investigated in future studies. [Table: see text]

Phase II multicenter study of chemotherapy (chemo)-naive castration-resistant prostate cancer (CRPC) not exposed to ketoconazole (keto), treated with abiraterone acetate (AA) plus prednisone

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 5046-5046 ◽  
Author(s):  
C. Ryan ◽  
E. Efstathiou ◽  
M. Smith ◽  
M. Taplin ◽  
G. Bubley ◽  
...  
Keyword(s):  
Performance Status ◽  
Median Number ◽  
Abiraterone Acetate ◽  
Castration Resistant Prostate Cancer ◽  
Ecog Performance Status ◽  
Androgen Withdrawal ◽  
Psa Response ◽  
Grade 3 ◽  
Hormonal Therapies ◽  
Ecog Ps

5046 Background: AA is a potent inhibitor of the enzyme CYP17, a major contributor to androgen biosynthesis. Keto is also known to inhibit this enzyme but AA is many-fold stronger in its action. 33 pts with progressive metastatic disease, normal organ function, ECOG performance status (PS) 0–1, and no prior chemo were enrolled. Pts with prior keto treatment were excluded. AA (1000 mg qd) plus prednisone (5mg bid) were administered orally in 28 day cycles. Methods: Results: At baseline median age was 71.0 (range 52–85) yrs and median PSA was 24.7 (range 7.1–1110.0) ng/mL;19/26 pts (73%) had an ECOG PS of 0 and 7/26 (27%) had PS of 1; the median number of prior hormonal therapies was 2; all pts were on LHRHa and 73% of pts had received anti-androgen, all of whom had undergone prior anti-androgen withdrawal. Pts were evaluated at each cycle for PSA response according to PSAWG criteria. 27 pts have available data for PSA response. Total maximal PSA declines of ≥30%, ≥50%, ≥90% were observed in 89% (24/27), 85% (23/27) and 41% (11/27) pts, respectively. Week 12 PSA declines displayed a similar and sustained trend: ≥30%, ≥50% and ≥90% PSA decline in 82%, 78%, and 26% of pts. Post-treatment ECOG PS score was 0 in 24 (92%) pts: 19% experienced improvement in PS (PS 1 to 0 in 5 pts) and 19/19 pts maintained a PS of 0; Median time to PSA progression has not been reached. Majority of adverse events were grades 1–2. Incidence of hypokalemia - 12%; HTN - 6%; edema - 15%. One pt experienced a grade 3 drug-related HTN. Conclusions: Abiraterone acetate plus prednisone has significant anti-cancer activity in patients with metastatic CRPC not previously treated with ketoconazole or chemotherapy, as demonstrated by declines in PSA and improvement in performance status, and is well-tolerated. [Table: see text]

Taxane-based chemotherapy in senior adults with metastatic castration-resistant prostate cancer (mCRPC): A prospective international registry.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e15122-e15122
Author(s):  
Jean-Pierre Droz ◽  
Eleni Efstathiou ◽  
Axel Heidenreich ◽  
Asif Yildirim ◽  
Paula Cabrera ◽  
...  
Keyword(s):  
Health Status ◽  
Clinical Benefit ◽  
Real Life ◽  
Geriatric Oncology ◽  
Older Men ◽  
Primary Therapy ◽  
Castration Resistant Prostate Cancer ◽  
International Registry ◽  
Psa Response ◽  
Grade 3

e15122 Background: Docetaxel every 3 weeks is the standard of care in mCRPC. Efficacy and toxicity of taxanes in older men (70+) is poorly documented. Their enrolment in randomized trials is limited by exclusion criteria. This prospective international registry evaluates taxane toxicity and efficacy in such men in real life. Methods: 333 men with mCRPC (median age 76) were evaluated. PS, grade 3-4 comorbidities (Cumulative Illness Scoring Rate-Geriatrics [CISR-G]), dependence (Activity Daily Living [ADL], Instrumental ADL [IADL]), nutritional status, primary therapy received and outcomes (overall survival (OS), progression-free survival (PFS), best clinical benefit [based on pain, analgesic consumption, PS], PSA response, toxicity) were collected. Follow-up under therapy was 6 months. Results: In all, 24.0% had PS ≥2, 13.5% grade 3-4 comorbidities, 21% were dependent in ≥1 IADL, 15.6% in ≥1 ADL and 12.8% had a weight loss ≥5% within the past 3 months. According to SIOG (International Society of Geriatric Oncology, BJU Int 2010; 106: 462-69) algorithm, 65.2% were fit, 13.5% vulnerable, 16.8% frail and 4.5% had terminal illness. Most patients (62.4%) had pain at enrolment. Primary therapy was a taxane in 58% (3-weekly, 84.4%; median, 5 months) and another therapy in 42%. Clinical characteristics of men treated by taxanes and other therapies were comparable. At 6 months, 91% were still alive with taxanes vs 81% with other therapies (HR [95% CI] 0.53 [0.30-0.93] p=0.027). Taxanes also significantly increased PFS (66% vs 50%, HR 0.55 [0.40-0.76], p<0.001), best clinical benefit (60% vs 36%, HR 2.05 [1.47-2.85], p<0.001) and PSA response ≥50% (52.5% vs 37.4%, p=0.018). Main grade 3-4 toxicities with taxanes were fatigue (17.1%), nausea/vomiting (14%), diarrhoea (8.8%), anaemia (7.8%), nail change (6.7%) and febrile neutropenia (2.6%). Conclusions: Taxanes appear the most effective first-line therapy in older men with mCRPC and show an acceptable and manageable toxicity. Further analyses will compare health status measured by SIOG algorithm to physician independent evaluation and identify the most pertinent geriatric predictors of health status.

Phase II study of docetaxel-prednisone (DP) in combination with metronomic cyclophosphamide (CTX) and celecoxib (C) as first-line treatment in castration resistant prostate cancer (CRPC) patients (Pts)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e16032-e16032
Author(s):  
A. Fontana ◽  
G. Bocci ◽  
L. Galli ◽  
L. Derosa ◽  
G. Minuti ◽  
...  
Keyword(s):  
Mononuclear Cells ◽  
Median Number ◽  
Primary Objective ◽  
Castration Resistant Prostate Cancer ◽  
Peripheral Blood Mononuclear ◽  
Castration Resistant ◽  
Psa Response ◽  
Psa Progression ◽  
Grade 3

e16032 Background: Metronomic oral CTX and C has demonstrated activity and a favourable toxicity profile in CRCP. Combination of such strategy with the standard DP could be of interest. Methods: Pts with CRPC received D 60 mg/sqm iv day 1 every 3 weeks up to 12 cycles and from day 2 continuously: P 5 mg po BID, CTX 50 mg po daily, and C 200 mg po BID. Primary objective is the percentage of pts free of progression at 6 months; secondary are: PSA levels decrease ≥ 50%, objective responses (RECIST), toxicities (NCI-CTC criteria) survival and pharmacodynamic evaluations. Results: To date 29 pts have been enrolled. Main pts characteristics are: median age 72 years (52–78 years), median PS 0 (0–2), median baseline PSA level 38,8 ng/mL (2.5–1309 ng/mL); main sites of disease: bone 23 pts (79%), lymphnodes 6 pts (21%), liver 1 pt (3,5%). Twenty-nine pts are evaluable for toxicity whereas 28 for PSA response (1 pt abandoned the study due to allergic reaction after first D administration). Median number of D cycles delivered is 10 (1–12) and median duration of metronomic CTX plus P and C is 224 days (35–874 days). Main grade 3 side-effects are: neutropenia (2 pt; 7%), thrombocytopenia, diarrhoea, stomatitis and onycholysis (1 pt; 3.5%). No grade 4 toxicities have been observed.The rate of pts free of progression at 6 months is 80%. Overall 18 pts (64%) showed a PSA decrease ≥ 50% and 23 pts (82%) showed any PSA decrease from baseline (range: 4%-99%of decrease). Four pts are evaluable according to RECIST criteria: we observed 1 CR, 2 SD and 1 PD. At a median follow up of 12,4 months median time to PSA progression is 11.6 months (95% CI 8,3–15). Conclusions: Metronomic CTX plus C in combination with DP is a feasible and tolerable regimen with a promising preliminary activity. The evaluation of plasma levels of thrombospondin-1 (TSP-1), VEGF, sVEGFR-2, VE-cadherin mRNA, and the expression of TSP-1 and VEGF in peripheral blood mononuclear cells, as potential surrogated markers of antiangiogenic activity of the combination, is ongoing. No significant financial relationships to disclose.

A phase II study of sunitinib (SU) for maintenance therapy in metastatic castration-resistant prostate cancer (mCRPC) after response to docetaxel (D).

2011 ◽  
Vol 29 (7_suppl) ◽  
pp. 151-151 ◽  
Author(s):  
B. J. Eigl ◽  
M. G. Trudeau ◽  
E. Winquist ◽  
K. N. Chi ◽  
M. Eliasziw ◽  
...  
Keyword(s):  
Maintenance Therapy ◽  
Phase Ii ◽  
Castration Resistant Prostate Cancer ◽  
Clinical Progression ◽  
Castration Resistant ◽  
Hand Foot Syndrome ◽  
Psa Response ◽  
Psa Progression ◽  
The Mean ◽  
Grade 3

151 Background: After treatment with D based chemotherapy, there is currently no standard therapy although new options are emerging. Due to its mechanism of action, acceptable toxicity profile and simple administration, SU has potential for therapeutic activity in the setting of maintenance therapy for patients with mCRPC who have responded to D based chemotherapy. Methods: Patients with mCRPC who had evidence of responding or stable disease at completion of D treatment were enrolled in this phase II multicentre trial. Patients received 50mg of SU daily on 4 week on/2 week off cycles. The primary endpoint was effect of SU maintenance on PFS. Because of potential effects of SU on PSA kinetics, clinical progression was defined independent of PSA. PSA response rate was a secondary endpoint. PSA-progression (PSA-P) was defined as a 25% PSA increase over baseline. Results: Thirteen patients have been enrolled and treated to date. Mean age was 63 years (47-76). ECOG scores of 0, 1, and 2 were reported for 4, 8 and 1 patients respectively. Mean number of prior cycles of D given was 9.5. A total of 28 cycles of SU were administered. A total of 291 adverse events (AEs) were recorded, of which 66%, 27%, and 7% were classified as Grades 1, 2, and 3, respectively. No Grade 4 AEs were seen. AEs were of a type and severity expected for SU. The most frequent grade 3 AEs were fatigue (n=3) and hand foot syndrome (n=3). No PSA responses have been documented. Most patients had immediate PSA increases without evidence of clinical progression. The mean PSAs increased by 159%, 396%, and 853% in Cycles 1, 2, and 3, respectively, corresponding to p-values of 0.18, 0.03, and 0.01 when compared to the PSA-P threshold of 25%. The trial will continue to complete its planned accrual of 26 evaluable patients and updated results, along with PFS, will be presented at the meeting. Conclusions: SU is well tolerated as maintenance therapy after D in men with mCRPC, with a predictable side-effect profile. PSA values after treatment with SU may not reflect progression in patients with mCRPCas significant increases were observed as early as Cycle 2 without clinical evidence of worsening disease. [Table: see text]

scholarly journals 345 Phase I/II trial of cabozantinib plus durvalumab in advanced gastroesophageal cancer and other gastrointestinal malignancies (CAMILLA): phase Ib safety and efficacy results

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A372-A372
Author(s):  
Anwaar Saeed ◽  
Robin Park ◽  
Junqiang Dai ◽  
Raed Al-Rajabi ◽  
Anup Kasi ◽  
...  
Keyword(s):  
Weight Loss ◽  
Dose Escalation ◽  
Kinase Inhibitor ◽  
Median Number ◽  
Gastrointestinal Malignancies ◽  
Phase Ib ◽  
Tolerability Data ◽  
Hand Foot Syndrome ◽  
Combined Positive Score ◽  
Grade 3

BackgroundCabozantinib is a multi-tyrosine kinase inhibitor primarily targeting VEGFR, MET, and AXL. These targets promote a tumor immune permissive microenvironment. Cabozantinib has demonstrated immunomodulatory properties & clinical synergy when paired with PD-L1 inhibitors such as durvalumab. Here, we present final results of phase Ib of the Camilla trial assessing cabozantinib plus durvalumab in advanced GE adenocarcinoma (GEA), colorectal cancer (CRC), and hepatocellular carcinoma (HCC). This is an investigator-initiated trial funded by Exelixis & Astrazeneca.MethodsPatients were administered cabozantinib + durvalumab in a dose escalation (3+3) then expansion to find the Dose Limiting Toxicities (DLTs), Recommended Phase 2 Dose (RP2D), ORR, PFS, and OS. Subgroup analysis was conducted to assess efficacy in patients with PD-L1 Combined Positive Score (CPS) ≥ 5. Dosing of cabozantinib was 20mg QD, 40mg QD, and 60mg QD PO in the 1st, 2nd, and 3rd cohorts. Dosing of durvalumab was 1500mg IV Q4W in all cohorts. DLT window was 28 days. Treatment beyond progression was allowed following modified RECIST v1.1 criteria.Results35 patients (14F, 21M), median age 53 years (range 27–79) were enrolled. 10 patients had GEA, 20 had CRC, and 5 had HCC; none had MMR deficiency. Median number of prior systemic therapies was 3 (range 0–3). No DLTs were observed during dose escalation. Per mature tolerability data, 11/14 patients receiving cabozantinib 60mg required dose-reduction post cycle 2 to 40mg. RP2D was determined to be cabozantinib 40mg QD plus durvalumab 1500mg Q4W. Of the 247 observed Treatment-Related Adverse Events (TRAEs), 10% (24) were grade≥3. Most common TRAEs were grade 1–2 fatigue (57%), nausea (43%), anorexia (40%), diarrhea (37%), transaminitis (34%), hand-foot syndrome (23%), & weight loss (23%). 2 patients each developed grade≥3 fatigue, weight loss, & abdominal pain. Overall, 30 pts were evaluable for efficacy. ORR 26.7%; DCR 83.3%; median PFS 4.5 months; 6-month PFS 36.7%; and median OS 9.1 months. 12 patients had PD-L1 CPS ≥5. In this subgroup, ORR 33.33%; DCR 91.67%; median PFS 6.13 months; 6-month PFS 50%; and median OS was not reached.ConclusionsCabozantinib plus durvalumab demonstrated promising efficacy and was fairly tolerated without new safety signals. High PD-L1 expression defined as CPS ≥ 5 was associated with improved efficacy & survival. The phase II multi-cohort part of the trial is currently ongoing.Trial RegistrationNCT03539822Ethics ApprovalThe study was approved by the participating site’s local IRB.ConsentAll study participants granted a written informed consent prior to treatment initiation.

Capecitabine As First-Line Treatment for Patients Older Than 70 Years With Metastatic Colorectal Cancer: An Oncopaz Cooperative Group Study

2005 ◽  
Vol 23 (13) ◽  
pp. 3104-3111 ◽  
Author(s):  
Jaime Feliu ◽  
Pilar Escudero ◽  
Ferrán Llosa ◽  
Matilde Bolaños ◽  
Jose-Manuel Vicent ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Elderly Patients ◽  
Combination Chemotherapy ◽  
Clinical Benefit ◽  
Overall Response Rate ◽  
Advanced Colorectal Cancer ◽  
First Line ◽  
Hand Foot Syndrome ◽  
Clinical Benefit Response ◽  
Grade 3

Purpose To determine the tolerability of capecitabine in elderly patients with advanced colorectal cancer (CRC). Patients and Methods Fifty-one patients with advanced CRC who were ≥ 70 years and considered ineligible for combination chemotherapy received oral capecitabine 1,250 mg/m2 twice daily on days 1 to 14 every 3 weeks. Patients with a creatinine clearance of 30 to 50 mL/min received a dose of 950 mg/m2 twice daily. Results A total of 248 cycles of capecitabine were administered (median, five cycles; range, one to eight cycles). The overall response rate was 24% (95% CI, 15% to 41%), including two complete responses (CR; 4%) and 10 partial responses (PR; 20%). Disease control (CR + PR + stable disease) was achieved in 67% of patients. The median times to disease progression and overall survival were 7 months (95% CI, 6.4 to 9.5 months) and 11 months (95% CI, 8.6 to 13.3 months), respectively. Of the 35 patients evaluated for clinical benefit response, 14 (40%; 95% CI, 24% to 58%) showed clinical benefit. Capecitabine was well tolerated. Treatment-related grade 3 and 4 adverse events were observed in only six patients (12%), and the most common events were diarrhea, hand-foot syndrome, and thrombocytopenia. One patient (2%) had an episode of angina, but no treatment-related deaths were reported. Conclusion Our findings suggest that capecitabine is effective and well tolerated in elderly patients with advanced CRC who are considered ineligible for combination chemotherapy.

Sign in / Sign up

Export Citation Format

Share Document