Whole brain radiation therapy (WBRT) with or without oral topotecan (TPT) in patients (pts) with non-small cell lung cancer (NSCLC) with brain metastases: Final analysis of an open-label phase III study.

2031 Background: Brain metastases from NSCLC occur in ~ 20% of pts and if untreated are associated with a 1 to 2 month overall survival (OS). Pre-clinical studies show that TPT added to radiation results in a radiotherapy enhancement ratio of 1.4 to 1.6. This trial was designed to test the effect of TPT co-administered with WBRT on OS. Methods: Pts with NSCLC and at least one measurable brain lesion were eligible. 472 pts were randomized to WBRT (3 Gy/day x 10 days) or WBRT and TPT 1.1 mg/m2/day for 10 days. Stratification factors: number of brain metastases and recursive partitioning analysis (RPA) class. Two weeks following WBRT, systemic anti-cancer therapy could be restarted at the treating physician’s discretion. Results: 468 pts were in the modified ITT population; 235 pts (WBRT + TPT) and 233 pts (WBRT+ best supportive care [BSC]). Of the 235 pts administered WBRT + TPT, 91 also received TPT after WBRT. The treatment arms were balanced for gender, age and smoking history. Median daily TPT dose was 2.25 mg. The median OS in the TPT arm was not better than in the BSC alone arm; 4.0 months (95%CI 3.4,4.8) vs.3.6 months (95%CI 3.0, 4.0), respectively; HR 0.88 (0.73, 1.07), P=0.1862. In the ITT population analysis by stratification variables, RPA class (I vs. II/III) was significantly different (HR 0.59) whereas baseline brain lesions (1 vs >1) were not (HR 0.97). Complete response and overall response rates in the WBRT+ TPT were 10% and 27%, and with BSC 5% and 26%, respectively. There were no differences in time to response or neurologic signs and symptoms. All adverse events (AEs) were more frequent in the TPT arm (87% vs. 64%) as were AEs related to study treatment (57% vs. 21%), serious AEs (41% vs. 18%) and fatal AEs (5% vs. 0%). The AEs more frequently seen in the TPT arm were typical for TPT (hematologic toxicity, febrile neutropenia and diarrhea). Conclusions: The study did not achieve its primary objective. There was no difference in OS achieved by the addition of TPT to WBRT. AEs were more common in the TPT arm. Clinical trial information: NCT00390806.

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Vandetanib with pemetrexed in patients with previously treated non-small cell lung cancer (NSCLC): An open-label, multicenter phase I study

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.7654 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 7654-7654 ◽

Cited By ~ 2

Author(s):

R. De Boer ◽

J. Vansteenkiste ◽

Y. Humblet ◽

J. Wolf ◽

L. Nogova ◽

...

Keyword(s):

Locally Advanced ◽

Primary Objective ◽

Phase Iii ◽

Electrolyte Imbalance ◽

Smoking History ◽

Qtc Interval ◽

Duration Of Treatment ◽

Open Label ◽

Short Baseline ◽

Once Daily

7654 Background: Vandetanib (ZD6474) is a once-daily oral anticancer drug that selectively inhibits VEGF-dependent tumor angiogenesis and EGFR- and RET-dependent tumor cell proliferation and survival. Methods: Eligible patients had locally advanced or metastatic NSCLC (stage IIIB/IV) after failure of 1st-line chemotherapy. An initial cohort of 10 patients received once- daily oral vandetanib (100 mg) with pemetrexed (500 mg/m2 i.v. infusion every 21 days). If <2 patients experienced a vandetanib- related dose-limiting toxicity (DLT), an additional cohort received vandetanib 300 mg + pemetrexed. The planned duration of treatment was =6 weeks. The primary objective of the study was to establish the safety and tolerability of vandetanib + pemetrexed. Secondary objectives included an assessment of pharmacokinetic (PK) interaction and preliminary assessment of efficacy (RECIST). Results: Twenty- one patients (14 male, 7 female; mean age 60 years, range 44–77) received vandetanib 100 mg + pemetrexed (n=10) or vandetanib 300 mg + pemetrexed (n=11). One DLT was reported in each cohort: QTc prolongation (>100 ms from baseline, but absolute QTc <500 ms) in a male patient who had electrolyte imbalance and short baseline QTc interval of 318 ms (100 mg cohort); and interstitial lung disease, which resolved after steroid therapy, in a Caucasian female patient with bronchoalveolar carcinoma and a long smoking history (300 mg cohort). The most common adverse events (AEs) were rash, anorexia, fatigue and diarrhea (all n=10; 48%). The most frequent CTC grade 3/4 AEs were increased gamma-glutamyltransferase (n=4), anorexia (n=3) and dyspnea (n=3), which are generally consistent with previous experience with vandetanib and pemetrexed as monotherapies. There was no apparent PK interaction between vandetanib and pemetrexed. In 18 patients evaluable for efficacy, there was one confirmed partial response (female; 100 mg cohort) and 13 stable disease =6 weeks. Conclusions: In patients with advanced NSCLC, vandetanib + pemetrexed was generally well tolerated, with no apparent PK interaction. A Phase III trial of vandetanib 100 mg + pemetrexed in 2nd-line NSCLC has begun. No significant financial relationships to disclose.

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TRLS-02. Trial in Progress: A Multicenter Phase 3 Study to Establish the Diagnostic Performance of 18F-Fluciclovine PET in Detecting Recurrent Brain Metastases after Radiation Therapy (REVELATE)

Neuro-Oncology Advances ◽

10.1093/noajnl/vdab071.020 ◽

2021 ◽

Vol 3 (Supplement_3) ◽

pp. iii5-iii5

Author(s):

Eugene Teoh ◽

Alain Chaglassian ◽

Nancy Tainer

Keyword(s):

Radiation Therapy ◽

Brain Metastases ◽

Diagnostic Performance ◽

Brain Mri ◽

Primary Objective ◽

Open Label ◽

Conventional Mri ◽

Specificity And Sensitivity ◽

Neurosurgical Intervention

Abstract Background Brain metastases occur in up to 40% of patients with cancer and are associated with poor prognosis and considerable levels of recurrence. Consequently, close follow-up with serial brain MRI is performed post-treatment to monitor for recurrent disease. Although conventional MRI (CE-T1-weighted and FLAIR/T2-weighted) is the recommended follow-up modality, it has poor specificity with limited ability to differentiate between true disease recurrence and treatment-related changes such as radiation necrosis. Therefore, alternative imaging options are sought in order to help physicians confidently diagnose treatment-related changes and thus reliably stratify the risk of continuation of a therapeutic regimen, especially given the morbidity associated with current treatments. Amino acid PET imaging agent, 18F-fluciclovine, has increased uptake in brain tumors relative to normal tissue and may be useful for detecting recurrent brain metastases. Methods NCT04410133 is a prospective, open-label, single-arm, single-dose (185 MBq ±20%) study with a primary objective to confirm the diagnostic performance of 18F-fluciclovine PET (read with conventional MRI for anatomical reference) for detection of recurrent brain metastases where MRI is equivocal. Approximately 150 subjects with solid tumor brain metastases who have undergone radiation therapy will be enrolled in this multicenter trial (~18 US sites) if they have a lesion considered equivocal on MRI that requires further confirmatory diagnostic procedures such as biopsy/neurosurgical intervention or clinical follow-up. Subjects will undergo 18F-fluciclovine PET <28 days after the equivocal MRI and 2–21 days pre-biopsy/neurosurgical intervention. Clinical follow-up will occur for 6m post-18F-fluciclovine PET. Secondary objectives include evaluation of subject- and lesion-level 18F-fluciclovine negative and positive percent agreement (equivalent to specificity and sensitivity respectively) for recurrent brain metastases, inter-reader and intra-reader agreement, and safety evaluations. Enrolment began in October 2020 and the trial is open at the time of submission.

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NEIM-02. TRIAL IN PROGRESS: A MULTICENTER PHASE 3 STUDY TO ESTABLISH THE DIAGNOSTIC PERFORMANCE OF 18F-FLUCICLOVINE PET IN DETECTING RECURRENT BRAIN METASTASES AFTER RADIATION THERAPY (REVELATE)

Neuro-Oncology Advances ◽

10.1093/noajnl/vdab112.023 ◽

2021 ◽

Vol 3 (Supplement_4) ◽

pp. iv6-iv7

Author(s):

Samuel T Chao ◽

Alain Chaglassian ◽

Nancy Tainer ◽

Eugene J Teoh

Keyword(s):

Radiation Therapy ◽

Brain Metastases ◽

Diagnostic Performance ◽

Brain Mri ◽

Primary Objective ◽

Open Label ◽

Conventional Mri ◽

Specificity And Sensitivity ◽

Neurosurgical Intervention

Abstract BACKGROUND Brain metastases occur in up to 40% of patients with cancer and are associated with poor prognosis and considerable levels of recurrence. Consequently, close follow-up with serial brain MRI is performed post-treatment to monitor for recurrent disease. Although conventional MRI (CE-T1-weighted and FLAIR/T2-weighted) is the recommended follow-up modality, it has poor specificity with limited ability to differentiate between true disease recurrence and treatment-related changes such as radiation necrosis. Therefore, alternative imaging options are sought in order to help physicians confidently diagnose treatment-related changes and thus reliably stratify the risk of continuation of a therapeutic regimen, especially given the morbidity associated with current treatments. Amino acid PET imaging agent, 18F-fluciclovine, has increased uptake in brain tumors relative to normal tissue and may be useful for detecting recurrent brain metastases. METHODS NCT04410133 is a prospective, open-label, single-arm, single-dose (185 MBq ±20%) study with a primary objective to confirm the diagnostic performance of 18F-fluciclovine PET (read with conventional MRI for anatomical reference) for detection of recurrent brain metastases where MRI is equivocal. Approximately 150 subjects with solid tumor brain metastases who have undergone radiation therapy will be enrolled in this multicenter trial (~18 US sites) if they have a lesion considered equivocal on MRI that requires further confirmatory diagnostic procedures such as biopsy/neurosurgical intervention or clinical follow-up. Subjects will undergo 18F-fluciclovine PET <42 days after the equivocal MRI and 1–21 days pre-biopsy/neurosurgical intervention. Clinical follow-up will occur for 6m post-18F-fluciclovine PET. Secondary objectives include evaluation of subject- and lesion-level 18F-fluciclovine negative and positive percent agreement (equivalent to specificity and sensitivity, respectively) for recurrent brain metastases, inter-reader and intra-reader agreement, and safety evaluations. Enrolment began in October 2020 and the trial is open at the time of submission.

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Analysis of the effect of crossover from placebo (PBO) to darolutamide (DARO) on overall survival (OS) benefit in the ARAMIS Trial.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.6_suppl.240 ◽

2021 ◽

Vol 39 (6_suppl) ◽

pp. 240-240

Author(s):

Neal D. Shore ◽

Karim Fizazi ◽

Teuvo Tammela ◽

Murilo Luz ◽

Manuel Philco Salas ◽

...

Keyword(s):

Treatment Effect ◽

Safety Profile ◽

Final Analysis ◽

Phase Iii ◽

Sensitivity Analyses ◽

Primary Analysis ◽

Open Label ◽

Double Blind ◽

Secondary Endpoints ◽

The Impact

240 Background: DARO is a structurally distinct androgen receptor inhibitor approved for the treatment of non-metastatic castration-resistant prostate cancer (nmCRPC) based on significantly prolonged metastasis-free survival compared with PBO (median 40.4 vs 18.4 months; hazard ratio [HR] 0.41; 95% confidence interval [CI] 0.34–0.50; P < 0.0001) and a favorable safety profile in the phase III ARAMIS trial. Following unblinding at the primary analysis, crossover from PBO to DARO was permitted for the subsequent open-label treatment phase. Sensitivity analyses were performed to assess the effect of PBO–DARO crossover on OS benefit. Methods: Patients (pts) with nmCRPC receiving androgen deprivation therapy were randomized 2:1 to DARO (n = 955) or PBO (n = 554). In addition to OS, secondary endpoints included times to pain progression, first cytotoxic chemotherapy, first symptomatic skeletal event, and safety. The OS analysis was planned to occur after approximately 240 deaths, and secondary endpoints were evaluated in a hierarchical order. Iterative parameter estimation (IPE) and rank-preserving structural failure time (RPSFT) analyses were performed as pre-planned sensitivity analyses to adjust for the treatment effect of PBO–DARO crossover. The IPE method used a parametric model for the survival times and iteratively determined the model parameter describing the magnitude of the treatment effect, whereas a grid search and non-parametric log-rank test were used for the RPSFT analysis. The IPE and RPSFT analyses both generated a Kaplan–Meier curve for the PBO arm that predicts what would have been observed in the absence of PBO–DARO crossover. Results: After unblinding, 170 pts (30.7% of those randomized to PBO) crossed over from PBO to DARO; median treatment duration from unblinding to the final data cut-off was 11 months. Final analysis of the combined double-blind and open label periods was conducted after 254 deaths (15.5% of DARO and 19.1% of PBO pts) and showed a statistically significant OS benefit for DARO vs PBO (HR 0.69; 95% CI 0.53–0.88; P = 0.003). Results from the IPE (HR 0.66; 95% CI 0.51–0.84; P < 0.001) and RPSFT (HR 0.68; 95% CI 0.51–0.90; P = 0.007) analyses were similar to those from the intention-to-treat population, showing that the impact of PBO–DARO crossover was small. Additional analyses accounting for the effect of PBO–DARO crossover will be presented. The safety profile of DARO continued to be favorable at the final analysis, and discontinuation rates at the end of the double-blind period remained unchanged from the primary analysis (8.9% with DARO and 8.7% with PBO). Conclusions: Early treatment with DARO in men with nmCRPC is associated with significant improvement in OS regardless of pts crossing over from PBO to DARO. The safety profile of DARO remained favorable at the final analysis. Clinical trial information: NCT02200614.

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OTHR-12. DRIVING RECOMMENDATIONS IN PATIENTS WITH NEWLY DIAGNOSED BREAST CANCER BRAIN METASTASES

Neuro-Oncology Advances ◽

10.1093/noajnl/vdz014.089 ◽

2019 ◽

Vol 1 (Supplement_1) ◽

pp. i20-i20

Author(s):

Leigh Swartz ◽

Heidi Egloff ◽

Aki Morikawa ◽

Catherine Van Poznak

Keyword(s):

Breast Cancer ◽

Brain Metastases ◽

Seizure Activity ◽

Descriptive Analysis ◽

Brain Lesion ◽

Primary Objective ◽

Develop Breast Cancer ◽

Newly Diagnosed ◽

Eligibility Criteria ◽

Breast Cancer Brain Metastases

Abstract BACKGROUND: Approximately 5% of all patients with breast cancer develop breast cancer brain metastases (BCBM). Medical and legal guidance on health conditions associated with driving may vary by state. The paucity of data to guide clinicians’ recommendations on driving in the setting of BCBM prompted this review of clinical practice. The primary objective is to determine the frequency of provider-documented driving recommendations with secondary objectives to define associated clinical factors. METHODS: University of Michigan’s (UM) DataDirect tool retrospectively searched records dated 11/30/2012 to 11/30/2018 using ICD 9 and 10 codes for breast cancer (C50.912, C50.911, C50.919, 174.9, 175.9) and for brain metastases (C79.31, D49.6, D43.2, 198.3, 239.6). Eligibility criteria were: age ≥ 18, BCBM, UM pathology confirmation of breast cancer, CNS imaging at time of diagnosis performed or reviewed at UM, and UM consultation with medical oncology, radiation oncology, neuro-oncology, neurosurgery, or neurology within 4 weeks of BCBM diagnosis. Chart abstraction included clinical and demographic factors for descriptive analysis. RESULTS: Only 87 of the 188 identified subjects (46%) met eligibility criteria. The most common exclusions were non-breast cancer brain lesion (n=40), neither UM imaging nor pathology (n=23) and no intra-parenchymal brain metastases (n=22). Of the 87 eligible subjects, 21 (24%) had documented recommendations against driving. Five of the 7 subjects with documented seizure history within 4 weeks of diagnosis also had documented recommendations against driving. There were 32 of 87 subjects on anti-epileptics of which 13 had documented driving recommendations. CONCLUSIONS: The minority of patients (24%) with newly diagnosed BCBM had a documented recommendation against driving. Seizure activity was strongly associated with documentation of driving recommendations. Other than seizure activity, general parameters regarding the safety of driving with newly diagnosed BCBM are not well defined. Prospective study is indicated to provide data supported recommendations regarding driving with BCBM.

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Tolerability and Efficacy of Bortezomib Added to CVP-R for Previously Untreated Advanced Stage Follicular Lymphoma: Interim Analysis of a Phase II Study by the NCIC Clinical Trials Group.

Blood ◽

10.1182/blood.v112.11.1576.1576 ◽

2008 ◽

Vol 112 (11) ◽

pp. 1576-1576 ◽

Cited By ~ 1

Author(s):

Laurie H Sehn ◽

David A Macdonald ◽

Sheldon H. Rubin ◽

Morel Rubinger ◽

Kevin R Imrie ◽

...

Keyword(s):

Follicular Lymphoma ◽

Phase Ii ◽

Interim Analysis ◽

Standard Dose ◽

Single Agent ◽

Acceptable Level ◽

Phase Iii ◽

Hematologic Toxicity ◽

Open Label ◽

Grade 3

Abstract Background: Despite recent improvements in therapy, follicular lymphoma (FL) remains incurable with standard treatment, warranting investigation of new approaches. Bortezomib, the first-in-class proteasome inhibitor has demonstrated promising efficacy as a single agent in heavily pretreated patients (pts) with FL. This is the first study to evaluate the safety and efficacy of the addition of bortezomib to cyclophosphamide, vincristine, prednisone and rituximab (CVP-R). Methods: This is a phase II multi-center open-label trial adding bortezomib (1.3 mg/m2 day 1&8) to standard dose C(750 mg/m2) V(1.4 mg/m2, capped at 2 mg) P(40 mg/m2 × 5) –R(375 mg/m2) for up to 8 cycles in pts with newly diagnosed stage III/IV FL requiring therapy. Planned accrual is 90 patients. A two-stage design was employed with a planned interim analysis of the first 28 patients to ensure an acceptable level of neurotoxicity (defined as less than 5/28 patients with grade 3/4 neurotoxicity after the first 4 cycles) and meaningful response rate (more than 12/28 patients with a complete response following 8 cycles), prior to enrolling remaining patients. Results: Median age of the first 28 patients was 55 years (range, 30–73). Fifty percent were male and 79% had stage IV disease. FLIPI score at study entry: low 14%, intermediate 43%, high 43%. Overall, the combination of bortezomib and CVP-R was extremely well tolerated. To date, no pts have developed grade 4 neurotoxicity and only 1/28 (4%) has developed grade 3 neurotoxicity within the first 4 cycles (neuropathic pain which resolved without need for treatment modification). The incidence of grade 1 and 2 neurotoxicity was 54% and 25% respectively. Only 3 pts discontinued therapy prematurely (2 pt refusal, 1 progressive disease). Ninety-four percent of planned bortezomib treatments in the first four cycles and 93% of vincristine doses were administered without dose reduction. Hematologic toxicity was mild, with no pts experiencing grade 3/4 anemia or thrombocytopenia. Only 2 episodes of febrile neutropenia occurred and no grade 3/4 infections were noted. Although it is too early to report on efficacy in this ongoing trial, response objectives for stage I have been met, and enrollment to stage 2 is underway. Conclusions: The addition of bortezomib to standard dose CVP-R is very well tolerated, with an acceptable level of neurotoxicity, without compromising the delivery of bortezomib or vincristine. This ongoing study will provide toxicity and efficacy data to facilitate the development of a planned phase III trial.

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Vandetanib with FOLFIRI in patients with advanced colorectal adenocarcinoma: an open-label, multicenter Phase I study

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.4085 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 4085-4085

Author(s):

M. Saunders ◽

E. Van Cutsem ◽

R. Wilson ◽

M. Peeters ◽

R. Smith ◽

...

Keyword(s):

Tyrosine Kinases ◽

Colorectal Adenocarcinoma ◽

Day Treatment ◽

Primary Objective ◽

Phase Iii ◽

Preliminary Evaluation ◽

Related Complication ◽

Open Label ◽

Once Daily ◽

Grade 3

4085 Background: Vandetanib (ZD6474) is a once-daily oral agent in Phase III development that selectively targets key signaling pathways in cancer by inhibiting VEGF, EGF and RET receptor tyrosine kinases. Methods: Patients with metastatic colorectal adenocarcinoma who were eligible for 1st- or 2nd-line chemotherapy received once-daily oral doses of vandetanib (100 mg) in combination with standard 14-day treatment cycles of FOLFIRI (irinotecan 180 mg/m2 1.5-hr and leucovorin 400 mg/m2 2-hr i.v. infusions, followed by 5-fluorouracil [5-FU] 400 mg/mg2 i.v. bolus and 5-FU 2400 mg/m2 46–48-hr i.v. infusion). If <2 of 6 evaluable patients (i.e., having completed 6 weeks of treatment) experienced a vandetanib- related dose-limiting toxicity (DLT), an additional cohort received vandetanib 300 mg + FOLFIRI. The primary objective of the study was to establish the safety and tolerability of vandetanib + FOLFIRI. Secondary objectives included an assessment of any pharmacokinetic (PK) interaction between vandetanib, irinotecan (SN-38) and 5-FU, and preliminary evaluation of efficacy (RECIST). Results: Twenty- one patients (12 male/9 female; mean age 53 years, range 33–72) received vandetanib 100 mg (n=11) or 300 mg (n=10) + FOLFIRI. Combination therapy was well tolerated at both vandetanib dose levels. There were no DLTs in the vandetanib 100 mg cohort, with one DLT of hypertension (CTC grade 3) with QTc prolongation in the 300 mg cohort. The most common adverse events (AEs; all grade 1/2) were diarrhea (n=20), nausea (n=12), fatigue (n=10) and alopecia (n=9); AEs =grade 3 reported in more than one patient were neutropenia (n=4, all grade 3), hypertension (n=3, all grade 3), catheter-related complication (n=2, both grade 3) and pulmonary embolism (n=2, both grade 4). There was no apparent PK interaction between vandetanib and irintotecan (SN-38) or 5-FU. Best overall responses in the 14 patients evaluable for efficacy were partial response (n=2), stable disease =8 weeks (n=9), and progressive disease (n=3). Conclusions: In patients with advanced colorectal adenocarcinoma, combining once-daily vandetanib (100 or 300 mg) with a standard FOLFIRI regimen was generally well tolerated. ZACTIMA is a trademark of the AstraZeneca group of companies. No significant financial relationships to disclose.

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SELECT: Randomized phase III study of docetaxel (D) or pemetrexed (P) with or without cetuximab (C) in recurrent or progressive non-small cell lung cancer (NSCLC) after platinum-based therapy.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.7502 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 7502-7502 ◽

Cited By ~ 4

Author(s):

Edward S. Kim ◽

Marcus A. Neubauer ◽

Allen Lee Cohn ◽

Lee Steven Schwartzberg ◽

Lawrence E. Garbo ◽

...

Keyword(s):

Objective Response ◽

Growth Factor Receptor ◽

Progression Free Survival ◽

Staining Intensity ◽

Primary Objective ◽

Phase Iii ◽

Open Label ◽

Duration Of Response ◽

Independent Review ◽

Secondary Endpoints

7502 Background: SELECT investigated whether the addition of C to standard chemotherapy improved progression-free survival (PFS) in patients (pts) with recurrent or progressive NSCLC after failure of platinum-based therapy. Methods: SELECT was a multicenter, open label, randomized phase III trial. Per investigator choice, pts received either P (500 mg/m2) or D (75 mg/m2) on day 1 and then were randomized within each group to chemotherapy plus C (400/250 mg/m2) (initial/weekly) or chemotherapy alone. Therapy was given for up to six 3-week cycles; pts randomized to C continued weekly monotherapy until disease progression or unacceptable toxicity. The primary objective was PFS for PC vs. P as determined by an Independent Review Committee (IRC). Secondary endpoints included overall survival (OS), objective response rate (ORR) and duration of response (DOR) by IRC, and safety. Preplanned subgroup analyses for epidermal growth factor receptor (EGFR) staining intensity by immunohistochemistry and histology were performed. Results for PC vs. P only are presented. Results: Between Jan 2005 and Feb 2010, 938 total pts were randomized. Baseline demographics were comparable between PC (n=301) and P (n=304): median age 64 years; male 60%; Caucasian 88%; KPS 80-100/60-70 84%/16%; squamous/non-squamous 24%/76%. Median PFS (months) PC: 2.89 and P: 2.76 (hazard ratio [HR] =1.03 [95% confidence interval (CI)=0.87-1.21]; p=0.76). Median OS (months) PC: 6.93 and P: 7.79 (HR=1.01 [95% CI=0.86-1.20]; p=0.86). ORR PC: 6.6% and P: 4.3% (odds ratio =1.59 [95% CI=0.78-3.26]; p=0.20). Median DOR (months) PC: 4.17 and P: 6.93 (HR=1.58 [95% CI=0.74-3.36]; p=0.24). There were no statistical differences in efficacy based on histology or EGFR staining intensity. More drug-related AEs/SAEs were observed in the PC arm, with differences mainly attributable to skin toxicities, GI (diarrhea/stomatitis), and hypomagnesemia. Conclusions: The addition of C to P did not improve efficacy in this pt population. Further biomarker analyses are planned. The safety profiles for C and P were consistent with existing data and no new safety signals were observed.

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Comparison of two doses of cabazitaxel plus prednisone in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) previously treated with a docetaxel (D)-containing regimen.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.tps4692 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. TPS4692-TPS4692 ◽

Cited By ~ 1

Author(s):

Mario A. Eisenberger ◽

Anne-Claire Hardy-Bessard ◽

Loic Mourey ◽

Paul N. Mainwaring ◽

Daniel Ford ◽

...

Keyword(s):

Prostate Cancer ◽

Progression Free Survival ◽

Phase Iii ◽

Hematologic Toxicity ◽

Castration Resistant Prostate Cancer ◽

Open Label ◽

Measurable Disease ◽

Previously Treated ◽

Grade 3 ◽

Ecog Ps

TPS4692^ Background: The phase III TROPIC study (NCT00417079) reported a significant improvement in overall survival (OS) for cabazitaxel (Cbz) + prednisone (P;CbzP) (25 mg/m2 IV Q3W/10 mg PO QD) vs mitoxantrone (M) + P (MP) (median OS 15.1 vs 12.7 mos; HR 0.70; P < 0.0001) in pts with mCRPC (also known as hormone-refractory prostate cancer) previously treated with a D-containing regimen. CbzP is approved by the FDA, EMA and other health authorities for the treatment of pts with mCRPC that has progressed after a D-containing regimen. Cbz toxicity is consistent with other taxanes; compared with M, more hematologic toxicities are reported (primarily Grade 3–4 neutropenia). Phase I/II studies identified 20 and 25 mg/m2 as recommended doses; 25 mg/m2 was selected for the phase III TROPIC study. As pooled data show Grade 3–4 neutropenia incidence is lower with Cbz < 25 mg/m2 (61%) vs ≥ 25 mg/m2 (74%), it is of interest to assess if reducing the Cbz approved dose in mCRPC lessens hematologic toxicity and is non-inferior in terms of efficacy. Methods: PROSELICA (NCT01308580) is a randomized, open-label, multinational, phase III study comparing 20 mg/m2 and 25 mg/m2 Cbz for efficacy and tolerability. Pts with a life expectancy > 6 mos, ECOG PS ≤ 2, histologically/cytologically confirmed metastatic prostate adenocarcinoma resistant to hormone therapy and previously treated with a D-containing regimen are eligible. Pts are randomized 1:1 to receive Cbz 20 mg/m² or 25 mg/m² IV Q3W + P 10 mg PO QD, treated until disease progression, unacceptable toxicity or withdrawal of consent (max 10 cycles), and stratified according to ECOG PS, measurable disease (yes/no) and region. The primary endpoint is OS (non-inferiority design). Secondary endpoints include safety, progression-free survival (PCWG2 criteria), PSA and pain progression and response, tumor response in pts with measurable disease and health-related quality of life. Cbz PK and pharmacogenomics will be assessed in pt subgroups. Planned enrollment is 1,200 pts. Study start was in May 2011; as of Jan 2012, 270 pts had been enrolled. The first DMC meeting recommended continuing the study without change.

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A randomized, multicenter, open-label, phase III study of the Bruton tyrosine kinase (BTK) inhibitor ibrutinib (PCI-32765) versus ofatumumab in patients (pts) with relapsed or refractory (RR) chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL): RESONATE.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.tps8619 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. TPS8619-TPS8619

Author(s):

John C. Byrd ◽

Jacqueline Claudia Barrientos ◽

Stephen Devereux ◽

Jennifer R. Brown ◽

Neil E. Kay ◽

...

Keyword(s):

Package Insert ◽

Cell Receptor ◽

Primary Objective ◽

Lymphocytic Leukemia ◽

Phase Iii ◽

Controlled Study ◽

Open Label ◽

Pivotal Phase ◽

Phase Iii Study ◽

Line Of Therapy

TPS8619 Background: Chemoimmunotherapy (CIT) treatment approaches such as FCR have markedly improved outcomes for CLL pts when administered as initial or second-line therapy. Despite this progress, virtually all pts relapse and effective salvage regimens that induce durable remissions or can be administered safely to elderly pts or those with comorbidities are lacking. BTK, an essential mediator of B-cell receptor signaling, is a novel target in CLL. Ibrutinib, a first-in class inhibitor of BTK, promotes apoptosis and inhibits proliferation, migration and adhesion in CLL cells. Phase II data of ibrutinib monotherapy in RR CLL demonstrated an estimated PFS and OS of 75% and 83% respectively at 26 months (Byrd Abst #189 ASH 2012). These findings confirmed BTK as an important target in CLL and supported initiation of a pivotal phase III study in pts with RR CLL/SLL. Methods: PCYC-1112-CA is an ongoing international Phase 3 randomized controlled study of ibrutinib versus ofatumumab for treatment of pts with RR CLL/SLL. The study is enrolling 350 planned pts in 9 countries. Pts are randomized 1:1 to receive ibrutinib 420 mg orally once daily or ofatumumab per the package insert at 300 mg for the first dose, then 2000 mg for a total of 12 doses over 24 weeks. Pts are stratified based on del 17p and disease refractory to purine analogs. Key inclusion criteria include RR CLL/SLL with >= 1 prior line of therapy including pts who experienced a short remission duration to purine analog based CIT, pts who are older or have comorbidities, and pts with del 17p. Pts must have active disease meeting criterion for requiring therapy and measurable nodal disease by CT. Key exclusion criteria include Richter’s transformation, stem cell transplantation within 6 months, GVHD or immunosuppression, platelet count <30,000 cells/ul or use of warfarin The primary objective of the study is PFS evaluated by an IRC. Other outcomes include ORR, OS, hematologic improvement, and safety. An independent DMC is monitoring the study. Clinical trial information: NCT01744691.

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