A phase I study of TRC105 (Anti-CD105 [endoglin] antibody) in metastatic castration resistant prostate cancer (mCRPC).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3043-3043
Author(s):  
Fatima H Karzai ◽  
Andrea Borghese Apolo ◽  
David Adelberg ◽  
Ravi A. Madan ◽  
James L. Gulley ◽  
...  
Keyword(s):  
Response Rate ◽  
Vascular Endothelial Cells ◽  
Transmembrane Protein ◽  
Performance Status ◽  
Progression Free Survival ◽  
Primary Objective ◽  
Endothelial Cell Proliferation ◽  
Clinical Activity ◽  
Castration Resistant Prostate Cancer ◽  
Ecog Performance Status

3043 Background: Pre−clinical and clinical evidence demonstrates an important role for angiogenesis in mCRPC biology. CD105 (endoglin) is a transmembrane protein expressed on the surface of proliferating vascular endothelial cells. The expression of CD105 is required for the formation of new blood vessels. TRC105 is a human/murine chimeric IgG1 kappa monoclonal antibody that binds to human CD105 (endoglin). It inhibits angiogenesis and tumor growth through inhibition of endothelial cell proliferation, antibody-dependent cellular cytotoxicity, and induction of apoptosis. The primary objective is to evaluate safety and identify the maximum tolerable dose (MTD) of TRC105. Secondary objectives include the assessment of TRC105 pharmacokinetics, PSA response rate, evaluation of progression free survival (PFS), overall response rate (ORR) and overall survival (OS). Methods: Patients with an ECOG performance status (PS) ≤ 2, progressive mCRPC and either chemotherapy-naïve or post-docetaxel treatment were eligible. Six cohorts of patients, on escalating dose levels, receive TRC105 intravenously at doses of 1, 3, 10, 15, or 20 mg/kg IV every 2 weeks (cohorts 1, 2, 3, 5, and 6) or 10 mg/kg IV weekly (cohort 4) on a 4 week cycle. Response is assessed with imaging studies every 2 months for the first four months and then every 3 months thereafter. Results: Sixteen patients are enrolled in cohorts 1-5. Median age is 65 (range 48-87), median ECOG PS is 1 (range 0−2), median Gleason score is 8 (range 6−10), median on−study PSA is 147.5 (range 0.1-3373), and median number of prior (non-hormonal) therapies is 3 (range 0−6). Median time on study is 16 weeks (range 8-28 weeks). One patient experienced a dose limiting toxicity (grade 4 vasovagal episode) in cohort 5. PSA declines were seen in 6 patients ranging from 20% to 57% from baseline. Ten out of 12 patients with measurable soft tissue disease achieved stable disease for at least two cycles. Conclusions: TRC105 is tolerated up to 15 mg/kg every two weeks with early evidence of clinical activity in mCRPC. An additional cohort (6), with dosage of 20 mg/kg, is currently under investigation. Accrual is ongoing to evaluate ORR, PFS, and OS in the phase II portion of this study.

A phase I study of TRC105 (anti-CD105 [endoglin] antibody) in metastatic castration-resistant prostate cancer (mCRPC).

2012 ◽  
Vol 30 (5_suppl) ◽  
pp. 117-117 ◽  
Author(s):  
Fatima H Karzai ◽  
Andrea Borghese Apolo ◽  
David E. Adelberg ◽  
Ravi Amrit Madan ◽  
James L. Gulley ◽  
...  
Keyword(s):  
Response Rate ◽  
Vascular Endothelial Cells ◽  
Transmembrane Protein ◽  
Performance Status ◽  
Progression Free Survival ◽  
Primary Objective ◽  
Endothelial Cell Proliferation ◽  
Clinical Activity ◽  
Castration Resistant Prostate Cancer ◽  
Ecog Performance Status

117 Background: Preclinical and clinical evidence demonstrates an important role for angiogenesis in mCRPC biology. CD105 (endoglin) is a transmembrane protein expressed on the surface of proliferating vascular endothelial cells. The expression of CD105 is required for the formation of new blood vessels. TRC105 is a human/murine chimeric IgG1 kappa monoclonal antibody that binds to human CD105 (endoglin). It inhibits angiogenesis and tumor growth through inhibition of endothelial cell proliferation, antibody-dependent cellular cytotoxicity, and induction of apoptosis. The primary objective is to evaluate safety and identify the maximum tolerable dose (MTD) of TRC105. Secondary objectives include the assessment of TRC105 pharmacokinetics, PSA response rate, evaluation of progression free survival (PFS), overall response rate (ORR) and overall survival (OS). Methods: Patients with an ECOG performance status (PS) ≤ 2, progressive mCRPC and either chemotherapy-naïve or post-docetaxel treatment were eligible. Five cohorts of patients, on escalating dose levels, receive TRC105 intravenously at doses of 1, 3, 10 or 15 mg/kg IV every 2 weeks (cohorts 1, 2, 3, and 5) or 10 mg/kg IV weekly (cohort 4) on a 4 week cycle. Response is assessed with imaging studies every 2 months for the first four months and then every 3 months thereafter. Results: Seventeen patients are enrolled in cohorts 1-5. Median age is 65 (range 48-87), median ECOG PS is 1 (range 0−2), median Gleason score is 8 (range 6−10), median on−study PSA is 147.5 (range 0.1-3373), and median number of prior (non-hormonal) therapies is 3 (range 0−6). Median time on study is 16 weeks (range 8-28 weeks). One patient experienced a dose limiting toxicity (grade 4 vasovagal episode) in cohort 5. PSA declines were seen in 6 patients ranging from 20% to 57% from baseline. Ten out of 12 patients with measurable soft tissue disease achieved stable disease for at least two cycles. Two patients remain on study (in cohort 5). Conclusions: TRC105 is tolerated up to 15 mg/kg every two weeks with early evidence of clinical activity in mCRPC. Accrual is ongoing to evaluate ORR, PFS, and OS in the phase II portion of this study.

A phase I study of TRC105 (anti-CD105 monoclonal antibody) in metastatic castration-resistant prostate cancer (mCRPC).

2011 ◽  
Vol 29 (7_suppl) ◽  
pp. 171-171 ◽  
Author(s):  
D. Adelberg ◽  
A. B. Apolo ◽  
R. A. Madan ◽  
J. L. Gulley ◽  
A. Pierpoint ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Response Rate ◽  
Performance Status ◽  
Primary Objective ◽  
Clinical Activity ◽  
Castration Resistant Prostate Cancer ◽  
Ecog Performance Status ◽  
Igg1 Monoclonal Antibody ◽  
Psa Response ◽  
Ecog Ps

171 Background: TRC105 is a human/murine chimeric IgG1 monoclonal antibody to CD105 (endoglin) that inhibits angiogenesis and tumor growth through inhibition of endothelial cell (EC) proliferation, antibody-dependent cellular cytotoxicity and induction of apoptosis. CD105 is highly expressed on proliferating vascular ECs. Preclinical and clinical evidence demonstrates an important role for angiogenesis in mCRPC biology. Methods: The primary objective is to evaluate safety and identify the maximum tolerable dose of TRC105. Secondary objectives include the assessment of TRC105 pharmacokinetics, PSA response rate and overall response rate (ORR). Eligibility requires ECOG performance status (PS) ≤ 2 and progressive mCRPC. Three cohorts of 3-6 patients receive TRC105 at doses of 1, 3 or 10 mg/kg IV over 1–4 hours every 2 weeks of a 4 week cycle. Premedications are dexamethasone, acetaminophen, famotidine, and diphenhydramine. PSA is evaluated prior to each treatment and response is assessed every 2 cycles with imaging studies. Results: Eight patients are enrolled in cohorts 1–3. Median age is 65 (range 47–84), ECOG PS 1 (1–2), Gleason score 8 (6–10), on–study PSA 201 (0.10 – 3,373), and number of prior therapies after gonadotropin-releasing hormone agonist or anti-androgen therapy 2.5 (0–6). Median time on study is 14 weeks (7–16). Dose-limiting toxicity was not observed. Grade 1 to 2 infusion reactions occurred in 4 patients. PSA declines were seen in both patients in cohort 3 (26% and 51% from baseline); each had progressed on docetaxel and at least one second-line agent. Five of 6 evaluable patients with measurable soft tissue disease achieved stable disease (2 in cohort 1, 2 in cohort 2 and 1 in cohort 3); the latter 3 patients in cohorts 2 and 3 remain on study. Conclusions: TRC105 is tolerated at doses up to 10 mg/kg every 2 weeks with early evidence of clinical activity in patients with mCRPC. Accrual is ongoing to evaluate higher doses and more frequent dosing. No significant financial relationships to disclose.

Clinical activity of enzalutamide against metastatic castration-resistant prostate cancer (mCRPC) in patients who have progressed on abiraterone acetate: The Princess Margaret experience.

2014 ◽  
Vol 32 (4_suppl) ◽  
pp. 159-159 ◽  
Author(s):  
Francisco Emilio Vera-Badillo ◽  
Raya Leibowitz-Amit ◽  
Arnoud Templeton ◽  
Jo-An Seah ◽  
Srikala S. Sridhar ◽  
...  
Keyword(s):  
Response Rate ◽  
Performance Status ◽  
Progression Free Survival ◽  
Median Number ◽  
Abiraterone Acetate ◽  
Clinical Activity ◽  
Castration Resistant Prostate Cancer ◽  
Ecog Performance Status ◽  
Psa Response ◽  
Metastatic Sites

159 Background: In men with mCRPC enzalutamide and abiraterone acetate have been shown individually to prolong survival after progression on chemotherapy with docetaxel. Little is known about the sequential use of enzalutamide and abiraterone. A PSA response rate of 8% and progression free survival (PFS) of 2.7 months has been reported for 38 men who received abiraterone following enzalutamide [Loriot, Ann Onc, 2013]. Here we report our experience with enzalutamide following abiraterone. Methods: We reviewed all patients with mCRPC treated with enzalutamide following abiraterone and docetaxel at our institution. Primary outcomes were PSA response rate (confirmed decline ≥ 50%) and time to treatment failure (TTF, defined as the time from treatment initiation to treatment discontinuation for any reason, including disease progression, treatment toxicity, patient preference, or death.). Data were analyzed using the Kaplan-Meier method. Results: Twenty-six patients were treated between August 2012 and July 2013. Median age was 72 years (range 56-88); 85% had ECOG performance status 0 or 1; metastatic sites included bone (N=25, 96%), lymph nodes (N=19, 73%) and visceral (N=1, 3.4%). Median number of prior cycles of docetaxel was 8 (range 1 – 12), 6 patients (29%) had previous exposure to ketoconazole, and median duration of previous abiraterone was 8.7 (range 1.4-22.7) months. Seven pts (27%) had a PSA response ≥ 50% and an additional 7 patients (27%) had a ≥ 30% PSA response. Median TTF on enzalutamide was 4.9 (95% CI 3.8-6.2) months. Reasons for discontinuation of enzalutamide were clinical and/or biochemical progression in 24 patients (92%), and toxicity (fatigue grade 3-4) in 3 patients (11.5%). An update of patient numbers and analysis will be presented at the meeting. Conclusions: Treatment of patients with mCRPC with enzalutamide after progression on docetaxel and abiraterone has modest clinical activity.

A phase Ib/II trial of indomethacin and enzalutamide to treat castration-resistant prostate cancer (CRPC).

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. TPS394-TPS394 ◽  
Author(s):  
Chong-xian Pan ◽  
Primo Lara ◽  
Christopher P. Evans ◽  
Mamta Parikh ◽  
Ralph de Vere White ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Clinical Trial ◽  
Response Rate ◽  
Performance Status ◽  
Progression Free Survival ◽  
Castration Resistant Prostate Cancer ◽  
Ecog Performance Status ◽  
Phase Ib ◽  
Androgen Synthesis ◽  
Psa Response

TPS394 Background: Enzalutamide (Enza) and abiraterone (Abi) are commonly used to treat CRPC. Resistance is the most common cause of treatment failure. We discovered that a critical steroidogenic enzyme AKR1C3 was significantly elevated and contributed to intratumoral androgen synthesis in Enza-resistant prostate cancer cells and tumors. Overexpression of AKR1C3 induced androgen receptor variant 7 (AR-V7) expression, while inhibition of AKR1C3 downregulated AR-V7. We then discovered that indomethacin (Indo) inhibited AKR1C3 activation and sensitized resistant CRPC cells to Enza and Abi. One patient accidentally took Indo and achieved biochemical as well as radiological response of his prostate cancer. These findings prompted us to design a clinical trial to test the combination of Indo with Enza for the treatment of CRPC and to study the underlying mechanisms of action and resistance. Methods: This investigator-initiated single-arm Phase Ib/II trial enrolls patients with progressive CRPC after Abi, adequate vital organ function, ECOG performance status 0-2, and serum testosterone < 50 ng/dl. Major exclusion criteria include prior Enza treatment, brain metastasis and history of seizure. In the Phase Ib cohort, patients receive Enza 160 mg po qd and Indo 50 mg po tid to determine toxicity. The Phase II expansion will enroll 26 patients with 21 evaluable patients. This sample size provides 90% power to detect, at the 0.05 level (1-sided), the difference between a PSA response rate of 50% expected with the study treatment and a historical control of 20% with Enza alone. Co-primary endpoints are safety and PSA response of ≥50% decrease. Secondary endpoints include overall response rate as determined by the Prostate Cancer Working Group 2 criteria (PCWG2), progression-free survival and overall survival. Molecular correlative studies are exploratory endpoints. Serum and intratumoral androgen levels, full-length AR, AR-V7 and AKR1C3 will be measured to assess the effect of the combination therapy. To date, 4 patients have been enrolled to the trial (clinicaltrials.gov Identifier No: NCT02935205; this trial is funded by DoD Prostate Cancer Research Program IMPACT award). Clinical trial information: NCT02935205.

Abiraterone acetate (AA) with or without cabazitaxel (CBZ) in treatment of chemotherapy naive metastatic castration-resistant prostate cancer (mCRPC).

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 84-84
Author(s):  
Susan F. Slovin ◽  
Karen E. Knudsen ◽  
Susan Halabi ◽  
Mark T. Fleming ◽  
Ana M. Molina ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Gene Networks ◽  
Radiographic Progression ◽  
Performance Status ◽  
Progression Free Survival ◽  
Risk Groups ◽  
Primary Objective ◽  
Castration Resistant Prostate Cancer ◽  
Ecog Performance Status ◽  
Castration Resistant

84 Background: Loss of retinoblastoma tumor suppressor (RB) function has been shown to lead to CRPC and is strongly associated with poor outcome. RB functions as a transcriptional repressor; as such, loss of RB causes de-repression of pro-tumorigenic gene networks, including deregulation of the androgen receptor (AR) locus, excessive AR production, and castration-resistant (ligand independent) AR activity that can bypass hormone therapy. Our hypothesis is that leveraging RB status can direct treatment decisions. The primary objective of the trial (NCT02218606) was to determine the radiographic progression free survival (rPFS) of AA/prednisone (AAP) with and without CBZ in mCRPC patients (pts) that have progressed on primary androgen deprivation therapy and no prior AR directed therapy or chemotherapy. Methods: This is a multicenter non-comparative randomized phase 2 trial. Pts were randomized 1:1 to AAP with crossover to CBZ upon AAP failure (Arm 1), or the combination of AAP + CBZ (Arm 2). Randomization was stratified by the CALGB 90401 prognostic risk groups. The primary endpoint was rPFS (time from randomization to radiographic progression or death, whichever occurs first). Arms were analyzed separately. Results: Between October 2014 and March 2019, 93 pts were accrued; 81 were randomized. Median age was 68 years and ECOG performance status was 0 or 1. Endpoints are shown in Table. Therapies were well tolerated. Conclusions: Results of AAP + CBZ (Arm 2) in chemotherapy naïve pts suggest that men may derive benefit from the earlier use of CBZ with acceptable toxicity, supporting further study of this combination in mCRPC pts. Circulating Tumor Cells are being analyzed for changes in RB/AR expression. Managed by: Prostate Cancer Clinical Trials Consortium; Funding: Sanofi US; Support: Prostate Cancer Foundation. Clinical trial information: NCT02218606. [Table: see text]

Phase II trial of single-agent ganetespib (STA-9090), a heat shock protein 90 (Hsp90) inhibitor in heavily pretreated patients with metastatic castration-resistant prostate cancer (mCRPC) post docetaxel-based chemotherapy: Results of a Prostate Cancer Clinical Trials Consortium (PCCTC) study.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 5085-5085 ◽  
Author(s):  
Elisabeth I. Heath ◽  
Mark N. Stein ◽  
Ulka N. Vaishampayan ◽  
Emmanuel S. Antonarakis ◽  
Glenn Liu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Clinical Trial ◽  
Cancer Cells ◽  
Performance Status ◽  
Single Agent ◽  
Progression Free Survival ◽  
Primary Objective ◽  
Castration Resistant Prostate Cancer ◽  
Ecog Performance Status ◽  
Stage 1

5085 Background: Hsp90 is a molecular chaperone required for the proper folding and activation of numerous client proteins and is critical to cell survival and proliferation. Ganetespib (G), a synthetic small molecule that binds to the ATP pocket in the N-terminus of Hsp90 causes the degradation of cellular proteins and ultimately death of cancer cells dependent on these proteins. G displays potent anticancer activity in prostate cancer cells. Methods: Eligible patients were ≥ 18 yrs old with ECOG performance status ≤ 2. Adequate hepatic, renal, and bone marrow function was required. Patients were treated with G 200 mg/m2 intravenously once weekly for 3 consecutive weeks followed by 1 off-week. The primary objective was to evaluate the 6-month progression-free survival (PFS). Secondary endpoints included overall safety and tolerability of G and overall survival. Exploratory markers including maspin, cytokeratins 8 and 18, and HDAC1 were obtained pre, during, and post G treatment. We sought ≥ 4 patients with ≥ 6 months PFS (a success) in Stage 1 of a 2-stage near-optimal Simon design. Results: 18 patients were enrolled at 4 institutions. The patients’ median age was 68 (range 51-82), 13 were Caucasian, 4 were African American, and 1 was Asian. Median PSA was 210.7 ng/mL (range 25.9 – 3,489 ng/mL). One patient never started therapy. Among the 17 treated patients, the median number of cycles was 2 (range 1-5). The most frequent Grade 3 toxicities were diarrhea (3 patients), fatigue (3), and dehydration (3). Prior therapy included abiraterone (8), sipuleucel-T (4), and other targeted therapy (4). With < 4 successes in Stage 1, the trial was terminated early. Median PFS was 1.9 months (90% CI: 1.7 – 2.7 months); median OS was 10.2 months (90% CI: 2.3 – 18.3 months). Exploratory markers have been evaluated and will be presented. Conclusions: Our study represents the first clinical trial of G in treating mCRPC patients. As a single agent therapy, G did not prolong PFS. Combination therapy is a consideration to improve therapeutic efficacy. Clinical trial information: NCT01270880.

Activity of a multitargeted, metronomic, and maximum-tolerated dose “chemo-switch” regimen in metastatic renal cell carcinoma (mRCC): A phase II study of sorafenib, gemcitabine (Gem), and metronomic capecitabine (Cap) in patients with advanced mRCC (SOGUG-02–06)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 5040-5040
Author(s):  
J. Bellmunt ◽  
J. Trigo ◽  
E. Calvo ◽  
J. Carles ◽  
J. Perez-Gracia ◽  
...  
Keyword(s):  
Vascular Endothelial Cells ◽  
Performance Status ◽  
Eastern Cooperative Oncology Group ◽  
Metronomic Chemotherapy ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Synergistic Activity ◽  
Duration Of Treatment ◽  
Ecog Performance Status ◽  
Multikinase Inhibitor

5040 Background: Maximal tolerated dose (MTD) chemotherapy followed by metronomic chemotherapy (low doses administered on a frequent schedule) acts on tumor vascular endothelial cells and enhances the antitumor effect of anti-angiogenic agents (Pietras et al. J Clin Oncol. 2007). This study investigated treatment of mRCC with Gem at MTD combined with metronomic Cap and the multikinase inhibitor sorafenib. Methods: Eligible patients had cytologically or histologically confirmed mRCC, Eastern Cooperative Oncology Group (ECOG) performance status ≤1 and no previous targeted therapy or chemotherapy, and were unsuitable for or intolerant to immunotherapy. Treatment consisted of six 3-week cycles of Gem 1000 mg/m2 i.v. (days 1 and 8), oral Cap 500 mg/m2 b.i.d. (days 1 to 14) and oral sorafenib 400 mg b.i.d. (every day), followed by sorafenib monotherapy (at the discretion of the investigator). Study endpoints included median progression-free survival (PFS, primary endpoint), disease control rate according to Response Evaluation Criteria in Solid Tumors, and safety. Results: Forty patients were enrolled and received at least one dose of treatment (median age 63 yrs, male n = 24, ECOG 0/1 n = 18/22, 1–2/>2 metastatic sites n = 31/9). Median duration of treatment was 6 months. Among 36 evaluable patients, 17 (47%) had a partial response and 17 (47%) achieved stable disease. Median PFS was 10.2 months (95% CI 7.6, 20.5). The most common adverse events (AEs) were fatigue/asthenia (78%) hand-foot syndrome (75%) and mucositis (69%). Most AEs were grade1/2, no grade 4 toxicities occurred. One patient had grade 5 dyspnea; 6 patients discontinued treatment for AEs. Conclusions: PFS and objective responses in this study were greater than those observed in previous studies with Gem and Cap or sorafenib monotherapy in patients with mRCC, while AEs remained moderate in the majority of patients. These findings confirm the synergistic activity of the “chemo-switch” concept seen in preclinical models. The combination of sorafenib with MTD Gem and metronomic Cap warrants further investigation in mRCC. [Table: see text]

A phase II study of S-1 for previously treated small cell lung cancer (SCLC)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e19074-e19074
Author(s):  
K. Kudo ◽  
F. Ohyanagi ◽  
A. Horiike ◽  
E. Miyauchi ◽  
I. Motokawa ◽  
...  
Keyword(s):  
Phase Ii ◽  
Response Rate ◽  
Performance Status ◽  
Single Agent ◽  
Progression Free Survival ◽  
Median Number ◽  
Ecog Performance Status ◽  
Treatment Regimens ◽  
Platinum Based Chemotherapy ◽  
Previously Treated

e19074 Background: S-1 is a novel oral 5-fluorouracil derivative that exhibits obvious activity against various tumor types including NSCLC. However, the effects of S-1 against SCLC have not been reported. The present phase II trial assesses the efficacy and safety of S-1 in previously treated SCLC patients. Methods: Eligible patients had pathologically documented SCLC that relapsed after platinum-based chemotherapy, ECOG performance status (PS) 0–2, and adequate bone marrow, kidney and liver function. Patients with untreated or symptomatic brain metastasis were excluded. Treatment comprised the oral administration of S-1 at 40 mg/m2 twice each day for 28 days every 6 weeks. The primary end point was the objective tumor response rate (RECIST). Secondary endpoints included progression-free survival and overall survival. Results: Twenty-six evaluable patients were enrolled (Simon's two-stage optimal design; α = 0.1; β = 0.1; P0 = 0.05; P1 = 0.25) with the following characteristics: male: female, 22/4; median age, 68 (33 - 79) y; PS0–1, n = 21; PS2, n = 5. The median number of prior treatment regimens was 2 (1–3). S-1 was administered for a mean of 1.3 cycles (1 - 5). One patient (3.8%) partially responded, 10 (38.5%) had stable and 15 (57.7%) had progressive disease. The overall response rate was 3.8% and the disease control rate was 42.3%. The median time to progression was 33 days. The median survival time was 8.0 months and the 1-year survival rate was 23%. This regimen was well tolerated. The common grade 3/4 toxicities included neutropenia (7.7%), leukopenia (7.7%), anemia (7.7%), hyponatremia (7.7%), rush (7.7%), infection (7.7%), and diarrhea (3.8%). None of the patients developed febrile neutropenia and no deaths were attributed to treatment. Conclusions: S-1 is well tolerated but has low activity as a single agent in previously treated patients with SCLC. No significant financial relationships to disclose.

Docetaxel-carboplatin chemotherapy in combination with cetuximab in patients with locally advanced or metastasized non-small cell lung cancer (NSCLC): Interim results of the nonrandomized phase II study TaxErb

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e19062-e19062
Author(s):  
J. R. Fischer ◽  
F. Griesinger ◽  
T. Fink ◽  
E. Buchholz ◽  
T. Salm ◽  
...  
Keyword(s):  
Phase Ii ◽  
Partial Remission ◽  
Response Rate ◽  
Phase Ii Study ◽  
Performance Status ◽  
Locally Advanced ◽  
Stage Iv ◽  
Progression Free Survival ◽  
Ecog Performance Status ◽  
Benefit Risk Assessment

e19062 Background: Combination chemotherapy with carboplatin-docetaxel has been shown to be effective and safe for patients with locally advanced or metastasized NSCLC. The monoclonal anti-EGRF antibody cetuximab has the potential to improve response rates and survival without a substantial increase in toxicity when given in combination with chemotherapy. Methods: Open, non-controlled phase II study with a planned sample size of 70 pts. Pts with locally advanced or metastasized NSCLC, ECOG performance status ≤ 2 and no prior systemic chemotherapy were treated with carboplatin AUC5 (d 1) q4w for 4–6 cycles and docetaxel 35 mg/m2 (d1, 8, 15) q4w; cetuximab 400 / 250 mg/m2 (d 1) q1w until progression or intolerable toxicity (12 month max.). The primary endpoint was response rate defined as complete or partial remission according to RECIST. Secondary endpoints were toxicity, 1 year survival, median and progression free survival. Results: Subject of the interims analysis were 27 pts (25 stage IV, 2 stage IIIb). ECOG 0/1/2 was 33.3%/59.3%/3.7% (1 no data). 63% had prior surgery, 93% prior radiotherapy and all had adjuvant or inductive chemotherapy. Pts received a mean of 3 ± 1.4 cycles docetaxel-carboplatin-cetuximab. 49 adverse events were grade 1–2 and 12 grade 3–5. Skin toxicity (49%; 95%CI: 30%-68%; 41% G1/2, 8% G3/4), dyspnoea (35%; 95%CI: 17%-53%) and diarrhoea (23%; 95%CI: 7 %-39%; 19% G1/2, 4% G3) were most frequent. 11 pts (41%) had toxicity leading to dose reduction. 0 pts had complete and 11 pts had partial remission resulting in a response rate of 40.7% (95%CI: 22%-59%) based on intention to treat. 6 pts had stable disease (22.2%; 95%CI: 7%-38%). 5 pts were not evaluable for response. Conclusions: The combination of carboplatin-docetaxel-cetuximab has an overall acceptable tolerability. With a preliminary response rate of 40.7% the benefit risk assessment was found to be favourable and the study was continued. [Table: see text]

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.

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