Phase II study of cabazitaxel (CAB) plus enzalutamide (ENZ) in metastatic castration-resistant prostate cancer (mCRPC).

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 86-86
Author(s):  
Julie Nicole Graff ◽  
Heather H. Cheng ◽  
Jacqueline Vuky ◽  
Joshi J. Alumkal ◽  
Dustin Kreitner ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Phase I ◽  
Phase Ii ◽  
Single Agent ◽  
Failure To Thrive ◽  
Castration Resistant Prostate Cancer ◽  
Eligibility Criteria ◽  
Psa Response ◽  
Pre Treatment ◽  
Grade 3

86 Background: There are six agents that improve survival in mCRPC, each administered as a single agent. Combinations of agents with distinct mechanisms of action have the potential to improve outcomes. Methods: We performed a multi-institution phase I/II study to examine safety and efficacy of CAB plus ENZ with mandatory granulocyte-colony stimulating factor support in mCRPC. Results: A sample size of 3 to 12 subjects for the phase I portion and 33 for the phase II portion provided 82% power to detect PSA response rate (decrease ≥90%) of 50% compared to the null hypothesis of 24%. The main eligibility criteria allowed prior abiraterone/prednisone (AAP) and docetaxel (in the metastatic hormone sensitive setting). Baseline characteristics: median age 69 years (47 - 82), median PSA 20.2 ng/dl (0.2 - 966.3); 7 subjects had visceral disease, 10 received prior AAP, and 8 received prior docetaxel. In the phase I portion, there were no dose limiting toxicities using CAB 25 mg/m2 IV Q3wks up to 10 cycles and ENZ 160 mg PO QD, hence this dosing was used for the phase II portion. 33 men with mCRPC were treated with CAB plus ENZ in the phase II arm. PSA response rates are listed in Table. Prior exposure to AAP decreased PSA response, but subjects who had prior AAP also had higher pre-treatment PSA. There were no treatment related deaths. Dose reduction of CAB to 20 mg/m2 was needed in 7 subjects. Over the course of the study, 14 Grade 3 adverse events occurred that were deemed possibly related to treatment: fatigue (n=2, 6%), febrile neutropenia (n=2, 6%), leukopenia (n=2, 6%), thrombocytopenia (n=2, 6%), anemia (n=1, 3%), hypertension (n=1, 3%), leukocytosis (n=2, 6%), fracture (n=1, 3%), failure to thrive (n=1, 3%). Conclusions: CAB plus ENZ was tolerable and associated with promising anti-tumor activity, particularly in abiraterone-naïve subjects. Further evaluation of this regimen is warranted. This project was managed by the Prostate Cancer Clinical Trials Consortium and funded by Astellas Inc. and Sanofi. Clinical trial information: NCT02522715. [Table: see text]

Phase I/II study of sorefenib and erlotinib for patients with recurrent glioblastoma (GBM) (NABTC 05–02)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 2005-2005
Author(s):  
M. Prados ◽  
M. Gilbert ◽  
J. Kuhn ◽  
K. Lamborn ◽  
T. Cloughesy ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Single Agent ◽  
Outcome Data ◽  
Recurrent Glioblastoma ◽  
Dose Finding ◽  
Pharmacokinetic Studies ◽  
Eligibility Criteria ◽  
Prior Chemotherapy ◽  
Grade 3

2005 Background: Single agent targeted therapy has been disappointing in GBM. Combination therapy simultaneously targeting both EGFR and the MAP kinase pathway may be more effective. Methods: The NABTC conducted a phase I/II study of sorafenib (VEGFR/PDGFR/Raf inhibitor) in combination with erlotinib (EGFR inhibitor) in recurrent GBM. Eligibility criteria included histologically proven GBM, radiologic progression, > 18 yrs old, KPS > 60, adequate bone marrow reserve, and organ function. There was no limit on the number of prior therapies for phase I and no more than two prior relapses for phase II. No enzyme-inducing antiepileptic drugs were allowed. Dose-finding used a standard 3 + 3 design and the MTD was defined as the dose with DLTs in 1/6 or fewer patients. The primary endpoint for the phase II component was PFS6 (p0 = 15%; p1 = 35%). A 2-stage design was used. If > 4 of the initial 19 patients achieved PFS6, an additional 14 patients would be accrued for a total of 33 patients. Results: In phase I, 17 patients were enrolled. Median age 50 years (35–69); median prior chemotherapy 1 (1–3). The initial doses were sorafenib 200 mg bid and erlotinib 100mg qd. MTD was 400 mg bid of sorafenib daily combined with 100 mg of erlotinib daily. At this dose 1/6 evaluable patients had a DLT (grade 4 lipase). Other grade 3 or 4 toxicities included transaminitis, hypertension, hypophosphatemia, and increased lipase. Pharmacokinetic studies showed no alterations in sorafenib PK, but no accumulation of erlotinib, suggesting a drug-drug interaction with sorafenib altering erlotinib metabolism or clearance. In phase II, 19 patients were accrued to stage I. Median age 51 years (30–75); median prior chemotherapy 2 (range 1–3). Phase II toxicity and outcome data are not yet mature but will be available at the time of presentation. Conclusions: This combination was moderately well-tolerated. MTD was below other combination phase I studies. Sorafenib affected the PK of erlotinib preventing drug accumulation. Phase II toxicity and outcome data will be reported. [Table: see text]

A phase I trial of AEZS-108 in castration- and taxane-resistant prostate cancer.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e15153-e15153
Author(s):  
Stephen V. Liu ◽  
Andrew V Schally ◽  
Tanya B. Dorff ◽  
Denice Tsao-Wei ◽  
Susan G. Groshen ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Phase I ◽  
Dose Level ◽  
Phase Ii ◽  
Rational Design ◽  
Phase I Trial ◽  
Lhrh Agonist ◽  
Castration Resistant Prostate Cancer ◽  
Eligibility Criteria ◽  
Correlative Studies

e15153 Background: The prognosis for patients with castration-resistant prostate cancer (CRPC) remains suboptimal and targeted therapies should be explored. One potential target is the receptor for luteinizing hormone-releasing hormone (LHRH), which is highly expressed on prostate cancer cells. AEZS-108 is an LHRH-cytotoxic hybrid whose rational design covalently couples an LHRH agonist and the cytotoxic doxorubicin. AEZS-108 exploits the presence of LHRH receptors to target delivery of the cytotoxic. We report the phase I trial of AEZS-108 in men with taxane-resistant CRPC. We also report correlative studies of a novel circulating tumor cell (CTC) capture device that will provide enumeration of CTCs and results from AEZS-108 internalization studies that exploit the auto-fluorescence of doxorubicin in captured CTCs. Methods: This is a single-arm, dose-escalation phase I study in men with CRPC to confirm the dose established in a completed phase I trial in females. Eligibility criteria included adequate organ function and progression of disease despite prior therapy with an LHRH agonist and at least one taxane-based regimen. Patients were required to discontinue LHRH agonists to avoid receptor competition. Due to potential cardiotoxicity, patients with an ejection fraction < 50% or prior exposure to doxorubicin or mitoxantrone were excluded. Pituitary function was closely monitored. Patients received AEZS-108 every 21 days for up to 6 cycles until progression or unacceptable toxicity. The primary endpoint was safety. Results: Enrollment began in November 2010 and is ongoing. Currently, 13 patients have been enrolled. The first two planned dose levels had no dose-limiting toxicities observed. Two patients on the third dose level experienced a dose limiting toxicity. The second dose level has been reopened for expansion. There have been no cardiac or pituitary toxicities. At the time of submission, a decrease in PSA was noted in 6 of the 13 patients. Final results detailing safety, response and the suggested dose for the phase II portion will be reported. All correlative studies will also be reported. Conclusions: In general, AEZS-108 has been well tolerated. The phase II portion of the study will begin once the MTD is established.

ARN-509 in men with high-risk nonmetastatic castration-resistant prostate cancer (CRPC).

2013 ◽  
Vol 31 (6_suppl) ◽  
pp. 7-7 ◽  
Author(s):  
Matthew Raymond Smith ◽  
Emmanuel S. Antonarakis ◽  
Charles J. Ryan ◽  
William R. Berry ◽  
Neal Shore ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
High Risk ◽  
Phase I ◽  
Phase Ii ◽  
Nuclear Translocation ◽  
Performance Status ◽  
Castration Resistant Prostate Cancer ◽  
Ecog Performance Status ◽  
Psa Response ◽  
Psa Progression

7 Background: ARN-509 is a novel second-generation anti-androgen that binds directly to the ligand-binding domain of the androgen receptor, impairing nuclear translocation and DNA binding. The Phase II portion of a multicenter Phase I/II study is evaluating the activity of ARN-509 in 3 distinct patient populations of men with CRPC (high risk non-metastatic CRPC, metastatic treatment-naïve CRPC, and progressive disease after abiraterone acetate). Preliminary results for the cohort of patients with high-risk non-metastatic CRPC are presented here. Methods: All patients had CRPC, no radiographic evidence of metastases (pelvic lymph nodes <3 cm below the iliac bifurcation were allowed), and high risk for disease progression based on PSA value ≥ 8 ng/mL within 3 months of enrollment and/or PSA doubling time ≤ 10 months. Patients received ARN-509 at the recommended Phase II dose of 240 mg/day, previously established in Phase I (Rathkopf et al, GU ASCO 2012). The primary endpoint was PSA response rate at 12 weeks according to the Prostate Cancer Working Group 2 Criteria. Secondary endpoints included safety, time to PSA progression and 1-year metastasis-free survival. PSA assessments were collected every 4 weeks and tumor scans were performed every 16 weeks. Results: Forty-seven patients were enrolled between November 2011 and May 2012. The median age was 71 years (range 51 to 88) and at baseline, patients presented with ECOG performance status 0 (77%), Gleason Score 8-10 (32%), and median PSA of 10.7 ng/mL. All patients received prior treatment with a LHRH analog with or without a first-generation anti-androgen. At a median treatment duration of 20 weeks, three patients discontinued the study. The most common treatment-related adverse events (AE) were fatigue (30%), diarrhea (28%), nausea (17%), rash (13%), and abdominal pain (11%). The incidence of Grade 3 AEs was 6.4%, and no seizures have been observed to date. The 12-week PSA response was 91% and the time to PSA progression has not been reached. Conclusions: In men with high-risk non-metastatic CRPC, ARN-509 is safe and well tolerated with promising preliminary activity based on high PSA response rates. Clinical trial information: NCT01171898.

IND 205B: A phase II study of the PI3K inhibitor PX-866 and continued abiraterone/prednisone in patients with recurrent or metastatic castration resistant prostate cancer (CRPC) with PSA progression on abiraterone/prednisone.

2015 ◽  
Vol 33 (7_suppl) ◽  
pp. 279-279 ◽  
Author(s):  
Sebastien J. Hotte ◽  
Anthony M. Joshua ◽  
Vamsee Torri ◽  
Robyn Jane Macfarlane ◽  
Naveen S. Basappa ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Ii Study ◽  
Single Agent ◽  
Objective Response ◽  
Castration Resistant Prostate Cancer ◽  
Multicentre Phase ◽  
Measurable Disease ◽  
Psa Response ◽  
Psa Progression ◽  
Grade 3

279 Background: PX-866 is an irreversible, pan-isoform inhibitor of Class I PI-3K. In part A of this study, PX-866 as a single agent was well tolerated and showed modest activity in CRPC but did not meet a priori benchmarks as a single agent in unselected patients (pts). As androgen receptor inhibition promotes PI3K activity in PTEN-loss PC models, the addition of PX-866 in patients whose PSA is rising on abiraterone acetate plus prednisone (AA+P) may reverse resistance and phase B of the study tested this hypothesis clinically. Methods: In this multicentre, phase II study, CRPC pts with PSA progression on AA+P received PX-866, 8mg daily on a 6-week cycle while continuing AA+P. Primary endpoint was lack of progression at 12 weeks (PCWG2 criteria). Secondary endpoints included PSA and objective response rates. PX-866 would be deemed worthy of further study if at least four of 25 pts were progression free at 12 weeks. Results: 25 pts were accrued and all are evaluable for toxicity and PSA response. Eleven pts had measurable disease of which 11 are evaluable for objective response. Median age was 72, ECOG PS was 0/1 in 10/15 pts. Eighteen pts received prior chemotherapy. Median number of cycles was 2 (range 1–3). 52% of pts received at least 90% of planned dose of PX-866. Most common adverse events (AEs) were fatigue (21 patients), diarrhea, (18), nausea (13), vomiting (11) and anorexia (12); one patient discontinued because of protocol therapy toxicity (grade 3 anemia). Other grade 3 AEs (one patient for each) were diarrhea, vomiting, fatigue, AST and ALT elevation and lymphocyte and platelet changes. Six pts were progression free at 12 weeks. No objective or PSA responses were seen. Of the pts with measurable disease, best objective response was stable disease in six (2.3-3.6m) and best PSA response was non-response in eight pts. Conclusions: The addition of PX-866 to AA+P in unselected pts progressing on AA+P shows no evidence of antitumour effects. Strategies to combine PI3K inhibition with AR targeted therapies should consider initiation earlier in the disease course and/or recruiting a selected population. Clinical trial information: NCT01331083.

Phase I/II study of sorafenib and temsirolimus for patients with recurrent glioblastoma (GBM) (NABTC 05–02)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 2006-2006 ◽  
Author(s):  
P. Y. Wen ◽  
T. Cloughesy ◽  
J. Kuhn ◽  
K. Lamborn ◽  
L. E. Abrey ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Single Agent ◽  
Recurrent Glioblastoma ◽  
Molecular Therapy ◽  
Dose Finding ◽  
Pharmacokinetic Data ◽  
Eligibility Criteria ◽  
Grade 3 ◽  
Recurrent Gbm

2006 Background: The activity of targeted molecular therapy with single agents has been disappointing in GBM. Combination therapy simultaneously targeting both the PI3k/Akt/mTOR and the MAP kinase pathway may be more effective. Methods: The North American Brain Tumor Consortium conducted a phase I/II study of sorafenib (VEGFR/PDGFR/Raf inhibitor) in combination with temsirolimus (mTOR inhibitor) in recurrent GBM. Eligibility criteria included histologically proven GBM, radiologic progression, > 18 years old, KPS > 60, adequate bone marrow reserve, and organ function. There was no limit on the number of prior relapses for phase I and no more than two prior relapses for phase II. No enzyme-inducing antiepileptic drugs were allowed. Dose-finding used a standard 3 + 3 design with the MTD defined as the dose with DLTs in 1/6 or fewer patients. The primary endpoint for the phase II component was PFS6 (p0 = 15%; p1 = 35%). A 2-stage design was used. If > 4 of the initial 19 patients achieved PFS6, an additional 14 patients would be accrued for a total of 33 patients. Results: In phase I, 13 patients were enrolled. Median age was 50 years (32–59); median prior chemotherapy 1 (1–3). The initial doses were sorafenib 200 mg bid and temsirolimus 25 mg intravenously once weekly. The MTD was 400 mg bid of sorafenib daily combined with 25 mg of temsirolimus weekly. At this dose 1/6 patients had a DLT (grade 3 thrombocytopenia). Other grade 3 or 4 toxicities included transaminitis, hypophosphatemia, fatigue, diarrhea, and hyperlipidemia. Pharmacokinetic data were similar to that for single agent sorafenib and temsirolimus suggesting that there were no significant interaction between the two drugs. In phase II, 19 patients were accrued to stage I. Median age 50 years (24–64); median prior relapses 1 (range 1–2). One patient was found not to have GBM on central review. No patient remained progression free at 6 months, although two patients stopped treatment prior to 26 weeks for other than progression (alternative therapy, cerebral ischemia). As result, the study was terminated and did not proceed to the second stage. Conclusions: The combination of sorafenib and temsirolimus was moderately well-tolerated but did not demonstrate sufficient efficacy in recurrent GBM to warrant further investigation. No significant financial relationships to disclose.

Phase I Trial of Docetaxel With Estramustine in Androgen-Independent Prostate Cancer

1999 ◽  
Vol 17 (3) ◽  
pp. 958-958 ◽  
Author(s):  
Daniel P. Petrylak ◽  
Robert B. Macarthur ◽  
John O'Connor ◽  
Gary Shelton ◽  
Timothy Judge ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Phase I ◽  
Response Rate ◽  
Area Under The Curve ◽  
Narcotic Analgesics ◽  
Pain Medications ◽  
Psa Response ◽  
Grade 3 ◽  
Recommended Phase Ii Dose ◽  
Androgen Independent

PURPOSE: To evaluate the toxicity, efficacy, and pharmacokinetics of docetaxel when combined with oral estramustine and dexamethasone in a phase I study in patients with progressive metastatic androgen-independent prostate cancer. PATIENTS AND METHODS: Thirty-four men were stratified into minimally pretreated (MPT) and extensively pretreated (EPT) groups. Estramustine 280 mg PO tid was administered 1 hour before or 2 hours after meals on days 1 through 5, with escalated doses of docetaxel from 40 to 80 mg/m2 on day 2. Treatment was repeated every 21 days. RESULTS: Thirty-four patients were assessable for toxicity and 33 for response. In the MPT patients, dose-limiting myelosuppression was reached at 80 mg/m2, with six patients experiencing grade 3/4 granulocytopenia. In EPT patients, escalation above 70 mg/m2 was not attempted. Fourteen MPT (70%) and six EPT (50%) patients had a ≥ 50% decline in serum PSA on two consecutive measurements taken at least 2 weeks apart. The overall 50% PSA response rate was 63% (95% confidence interval [CI], 28% to 81%). Of the 18 patients with bidimensionally measurable disease, five (28%; 95% CI, 11% to 54%) achieved a partial response. At the time of entry onto the study, 15 patients required narcotic analgesics for bone pain; after treatment, eight (53%) discontinued their pain medications. The area under the curve for docetaxel increased linearly from 40 to 70 mg/m2. At 80 mg/m2, the measured area under the curve was 8.37 (standard deviation, 0.724), which was significantly higher than the previously reported values. CONCLUSION: The recommended phase II dose of docetaxel combined with estramustine is 70 mg/m2 in MPT patients and 60 mg/m2 in EPT patients. This combination is active in men with androgen-independent prostate cancer.

A Phase II Multicenter Study of the Histone Deacetylase Inhibitor (HDACi) Abexinostat (PCI-24781) in Relapsed/Refractory Follicular Lymphoma (FL) and Mantle Cell Lymphoma (MCL)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 55-55 ◽  
Author(s):  
Andrew M. Evens ◽  
Julie M Vose ◽  
Wael Harb ◽  
Leo I. Gordon ◽  
Robert Langdon ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Safety Profile ◽  
Tumor Size ◽  
Phase Ii Study ◽  
Cell Lymphoma ◽  
Single Agent ◽  
Employment Equity ◽  
Equity Ownership ◽  
Grade 3

Abstract Abstract 55 Background: Abexinostat (PCI-24781) is a novel oral pan-HDACi that has previously demonstrated potent preclinical activity in lymphoma cell lines and animal models (Evens et al, Clin Ca Res 2009) as well as a tolerable safety profile in phase I solid tumor clinical studies (Undevia et al, ASCO 2008). In a phase I single-agent clinical trial in patients (pts) with multiply relapsed/refractory lymphoma and leukemia, anti-tumor activity was noted in FL and MCL; 4/4 FL pts showed durable clinical benefit with median time on treatment of >8 months; 1 of 2 MCL pts had a complete remission (CR) and remains on treatment for >3 years. Based on these encouraging single-agent abexinostat data, a phase II extension study was completed in relapsed/refractory FL and MCL. Methods: The primary objective of this phase II study was objective response rate (ORR, complete [CR] and partial remission [PR]), while reduction in tumor size (CR + PR + stable disease) and safety were also examined. Abexinostat was given orally twice daily at 45mg/m2 on a 4-week cycle for 7 days/week every other week, which is the previously established dose and schedule identified in the phase I study. For pharmacodynamic correlative analyses, tubulin and histone acetylation were measured in peripheral blood mononuclear cells (PBMCs) at pre-dose and 4 hours after the first dose of abexinostat. Results: A total of 30 pts were enrolled (n=16 FL and n=14 MCL pts) of which 25 were response-evaluable. The median age was 67 years (36–81) and the median prior therapies were 3 (1–5), 77% of which were rituximab-containing and one-third (33%) had undergone prior autologous stem cell transplant (31% FL, 36% MCL). The ORR in all pts was 48% (12/25). A reduction in tumor size was observed in 86% (12/14) of FL pts, while the ORR in FL was 64% (9/14); the FL intent-to-treat ORR was 56%. With a median follow-up of 10.3 months (1.2–20.9), the progression-free probability was 86% in FL pts. Furthermore, the median duration of response (DOR) in FL pts has not been reached, as 5 responders remain on study. Notably, 4 FL pts were on treatment for over 16 months. Among MCL pts, reduction in tumor size was noted in 27% (3/11), while the ORR was similar at 27% (3/11). The median progression-free survival (PFS) in MCL pts was 4 months (1–12), while the DOR in the 3 responding patients were 2+, 3, and 6+ months. Therapy was overall well tolerated. The most common treatment-related adverse events (AEs) of any grade (> 20% incidence) include: nausea (60%), fatigue (57%), diarrhea (50%), thrombocytopenia (37%), vomiting (30%), anemia (27%), decreased appetite (23%), dysgeusia (20%) and neutropenia (20%). The most common grade 3/4 related AEs (> 5% incidence) were thrombocytopenia (17%), neutropenia (13%), fatigue (13%), and anemia (7%). There were no deaths reported on the study. Pharmacodynamic analyses revealed that a majority of pts had increased tubulin acetylation in PBMCs, however this finding did not correlate with response or toxicity. Conclusion: In this phase II study, the novel pan-HDACi, abexinostat, was clinically active and overall well tolerated in relapsed/refractory B-cell lymphoma. The safety profile was consistent with this class of agents with <20% of subjects experiencing grade 3/4 cytopenias (during the course of prolonged treatments). Moreover, there was significant clinical activity noted in FL with an ORR of 64%, which included several durable responses in this multiply-relapsed pt population. Further examination of single-agent abexinostat in FL is warranted. Disclosures: Off Label Use: PCI24781 is not FDA approved; it is an investigational agent. Plasencia:Pharmacyclics: Employment, Equity Ownership. Sirisawad:Pharmacyclics: Employment, Equity Ownership. Yue:Pharmacyclics: Employment, Equity Ownership. Luan:Pharmacyclics: Employment, Equity Ownership. Siek:Pharmacyclics: Employment, Equity Ownership. Zhou:Pharmacyclics: Consultancy. Balasubramanian:Pharmacyclics: Employment, Equity Ownership.

A phase II study evaluating the efficacy and safety of single agent IMC A12, a monoclonal antibody (MAb), against the insulin-like growth factor-1 receptor (IGF-IR), as monotherapy in patients with metastastic, asymptomatic castration-resistant prostate cancer (CRPC)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 5142-5142 ◽  
Author(s):  
C. Higano ◽  
J. Alumkal ◽  
C. J. Ryan ◽  
E. Y. Yu ◽  
T. M. Beer ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Antitumor Activity ◽  
Single Agent ◽  
Castration Resistant Prostate Cancer ◽  
Radiologic Evaluation ◽  
Castration Resistant ◽  
Disease Stabilization ◽  
Human Igg1 ◽  
Grade 3 ◽  
Transient Elevation

5142 Background: IGF-IR-mediated signaling contributes to prostate cancer carcinogenesis and pathogenesis and may be associated with hormone resistance. IMC-A12 is a fully human IgG1 MAb that specifically targets the IGF-IR and inhibits ligand binding and signaling. In xenografts, IMC-A12 inhibits growth of both androgen-dependent and -independent prostate cancer. This phase 2, multicenter study was designed to assess the safety and antitumor activity of IMC-A12 in asymptomatic pts with metastatic CRPC who were chemotherapy-naive. Methods: Pts received IMC-A12 10 mg/kg IV every 2 wks; until evidence of progressive disease (PD), intolerable toxicity, or other withdrawal criteria were met. Radiologic evaluation was performed every 8 wks. PD by bone scan required at least 2 new lesions with confirmation at subsequent imaging per PCWG2. Results: 19 of 31 pts treated have discontinued IMC-A12, 12 due to PD. 9 of 31 pts experienced disease stabilization for ≥6 mos (range: 7.4–12.5 mos), 5 pts (3 with PSA reduction) continue on IMC-A12. The most common AEs possibly or probably related to IMC-A12, were fatigue (25.8%) and hyperglycemia (19.4%). In 4 pts cases of Grade 3 hyperglycemia was treatment related none requiring discontinuation of IMC-A12; 1 pt required insulin but continued on study. Approximately 70% of pts experienced at least transient elevation of nonfasting glucose to above normal range. Other AEs grade ≥3 at least possibly related to IMC-A12 were one case each of thrombocytopenia (requiring IMC-A12 discontinuation), hyperkalemia, fatigue, pneumonia (resulting in death), and Grade 4 pharmacokinetic and pharmacodynamic analayses are pending leukoencephalopathy (probably related; requiring IMC-A12 discontinuation). Pharmakinetic and pharmacodynamic analyses are pending. Conclusions: IMC-A12 monotherapy appears well tolerated in pts with metastatic asymptomatic CRPC. As in phase I, hyperglycemia was largely asymptomatic and manageable. Disease stabilization for > 6 months in 9 of 31 pts suggests that IMC- A12 may have modest antitumor activity. Additional studies of IMC-A12 in CRPC are planned. [Table: see text]

Ixabepilone, mitoxantrone, and prednisone in patients with metastatic castration-resistant prostate cancer refractory to docetaxel-based therapy: A phase II study of the DOD Prostate Cancer Clinical Trials Consortium

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 5058-5058
Author(s):  
E. Small ◽  
A. Harzstark ◽  
V. K. Weinberg ◽  
D. C. Smith ◽  
P. Mathew ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Clinical Trials ◽  
Phase Ii ◽  
Vasovagal Syncope ◽  
Objective Response ◽  
Study Drug ◽  
Cancer Clinical Trials ◽  
Second Line ◽  
Castration Resistant Prostate Cancer ◽  
Grade 3

5058 Background: Mitoxantrone (M) plus prednisone (P) and ixabepilone (Ix) each have modest, non cross-resistant activity as second line chemotherapy regimens in docetaxel-refractory patients with CRPC. These agents were therefore combined in a phase I study which demonstrated anti-cancer activity and defined the recommended phase II dose used in this trial. Methods: Patients with metastatic CRPC and progression after 3 or more cycles of docetaxel were enrolled in a phase II multicenter study of the combination of prednisone 5 mg BID, Ix (35 mg/m2) and M (12 mg/m2) administered intravenously on day 1 every 21 days, with pegfilgrastim (6 mg on day 2) support. Results: To date, 43 pts have been enrolled and have received a median of 4 cycles. Of 37 patients currently evaluable for response, 14 (38%; 95% CI: 22–55%) have had a confirmed ≥50% decline in PSA and 19 (51%; 95% CI 34–68%) have had a confirmed ≥30% decline in PSA. Two of 15 patients with evaluable measurable disease (13%) have had a RECIST-defined objective response. All 43 patients are evaluable for toxicity. Grade 3 or 4 neutropenia was seen in 6 pts (17%) and grade 3 or 4 thrombocytopenia was seen in 3 (8%). Nonhematologic grade 3/4 events possibly related to study drug have included grade 3 fatigue (3 pts), grade 3 pneumonia (2 pts), and grade 3 atrial fibrillation, grade 4 myocardial infarction, grade 4 prostatitis, grade 3 nausea/vomiting, grade 3 neuropathy, grade 3 elevated transaminases, grade 3 dizziness, grade 3 dehydration, grade 3 shortness of breath, and grade 4 vasovagal syncope (1 pt each). Grade 2 neuropathy has been seen in 4 patients. Conclusions: The Ix, M, P regimen is active as second-line therapy in CRPC patients with progressive disease after docetaxel therapy and is reasonably well tolerated. Further investigation of this regimen is warranted. This study was supported in part by CTEP/NCI and the DOD Prostate Cancer Clinical Trials Consortium. [Table: see text]

Phase I/II study of erlotinib and temsirolimus for patients with recurrent malignant gliomas (MG) (NABTC 04–02)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 2004-2004
Author(s):  
S. M. Chang ◽  
J. Kuhn ◽  
K. Lamborn ◽  
T. Cloughesy ◽  
I. Robins ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Single Agent ◽  
Malignant Gliomas ◽  
Mtor Inhibitors ◽  
Pharmacokinetic Data ◽  
Eligibility Criteria ◽  
Egfr Amplification ◽  
The North ◽  
Anaplastic Gliomas

2004 Background: Glioblastomas (GBM) frequently have EGFR amplification/mutations and inactivation of PTEN. Although single agent EGFR and mTOR inhibitors have limited activity, combinations of these agents may be more effective. Methods: The North American Brain Tumor Consortium conducted a phase I/II study of the EGFR inhibitor erlotinib in combination with the mTOR inhibitor temsirolimus in recurrent MG. Eligibility criteria were histologically proven GBM and anaplastic gliomas (AG), radiologic progression, >18 years old, KPS >60, adequate bone marrow and organ function. There was no limit on the number of prior relapses for phase I and no more than two prior relapses for phase II. Patients must not be receiving enzyme-inducing antiepileptic drugs. The dose of erlotinib was 150 mg/d in phase I and titrated up to maximum of 200mg/d in phase II depending on tolerability. Patients initially received temsirolimus 50 mg i.v. once weekly and the dose adjusted based on toxicities. Escalation was performed in groups of three. MTD was defined as the dose with 1/6 or fewer patients with dose-limiting toxicities (DLTs). Primary endpoint for the phase II component was PFS6. Results: In phase I, 22 patients were enrolled (15 GBM; 7 AG). Median age was 54 years (26–74); median KPS 90 (70–100); median prior relapses 1 (0–3). The MTD was determined to be 150 mg of erlotinib daily combined with 15 mg of temsirolimus weekly. DLTs were rash, mucositis, and liver function abnormalities. Pharmacokinetic data were similar to that for single agent erlotinib and temsirolimus; there was no interaction between the two drugs. AUC accumulation ratios between cycle 1 and 2 for erlotinib and OSI-420 were 3.6 and 4.6, respectively. In phase II, there were 56 patients (including 12 phase I patients treated at the MTD): 40 GBM; 16 AG, median age 47 years (20–72); median KPS 90 (range 60–100), median prior relapses 1 (range 1–3). Six patients discontinued therapy as a result of toxicities. For GBM patients, there was no PR, 30% SD, and PFS6 was 12.5%. For AG patients there was 12.5% PR, 12.5% SD, and PFS6 was 6.25%. Conclusions: The combination of erlotinib and temsirolimus was associated with a higher than expected incidence of toxicities and had minimal activity in recurrent MG. [Table: see text]

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