International Expanded Access Program Research Articles

CheckMate 743: A Glimmer of Hope for Malignant Pleural Mesothelioma

CheckMate 743: A Glimmer of Hope for Malignant Pleural Mesothelioma

108O - Treatment duration of brigatinib in patients enrolled in the international expanded access program (EAP)

108O - Treatment duration of brigatinib in patients enrolled in the international expanded access program (EAP)

C19 - Analysis of overall survival by number of radium-223 injections received in an international expanded access program (iEAP)

C19 - Analysis of overall survival by number of radium-223 injections received in an international expanded access program (iEAP)

Analysis of overall survival by number of radium-223 injections received in an international expanded access program (iEAP).

5082Background: In ALSYMPCA, 6 injections (inj) of radium-223 (Ra-223) at 50 kBq/kg v placebo, improved overall survival (OS) in patients (pts) with metastatic castration-resistant prostate cancer ...

Potential Value of Gleason Score in Predicting the Benefit of Cabazitaxel in Metastatic Castration-Resistant Prostate Cancer

This study aimed to identify predictive/prognostic factors in castration-resistant prostate cancer patients treated with cabazitaxel. Patients were enrolled from March 2011 to December 2011 in an international expanded access program. In January 2012, when cabazitaxel became commercially available, a prospective study was initiated at University Federico II of Naples and at Rionero in Vulture Hospital. Forty-seven patients were enrolled in this study. Patients received a median of nine cycles of cabazitaxel. Median progression-free survival was 7.0 months (95% CI: 5.7-8.0). Seventeen patients were still alive at the time of the analysis, with a median overall survival of 14 months (95% CI: 11-16). At multivariate analysis, a higher Gleason score (≥ 8) appeared to be associated with prolonged progression-free survival (hazard ratio: 0.36; 95% CI: 0.18-0.72); however, the higher Gleason score showed no statistical impact on overall survival. We hypothesize that the Gleason score has the potential to be incorporated in the clinical decision-making process for definition of treatment strategy in docetaxel-pretreated castration-resistant prostate cancer patients. We encourage further experimentation in this setting.

Ipilimumab for advanced, refractory melanoma: A report of the Israeli cohort of expanded access program.

e20039 Background: As the first agent to show survival advantage in metastatic melanoma, Ipilimumab (Yervoy, BMS) is being gradually introduced into health services worldwide. It's unique immune mediated side effects requires the incorporation of follow-up guidelines to prevent toxic sequella. We report on safety and efficacy results of refractory melanoma patients (pts) treated on an international expanded access program of Ipilimumab. Methods: Between 4/2010 and 12/2011 183 pts were treated. Pts received Ipilimumab 3 mg/kg q3w for 4 doses. Pts with evidence of clinical benefit at week 12 (CR, PR or SD), were eligible for re-induction upon progression. Results: All pts were pretreated for metastatic disease (median:1 line,range 1-5). 140 pts(77%) had M1c disease, 63 pts(34%) had brain metastasis and 84 (46%) had LDH above ULN, reflecting poor prognostic characteristics of this cohort. Patients received 3.6 doses of Ipilimumab on average. 11% received less than 4 cycles due to toxicity. Grade 3/4 immune-related adverse events were noted in 19.6% with the most common all grades toxicity being diarrhea (17.5%), pruritus (14%) rash (13%) and fatigue (8.7%). Grade 5 toxicity was noted in 4 patients (2%). Five pts were treated with anti TNF antibodies (Infliximab) for steroid resistant toxicity. Objective responses were noted in 16 pts (8.7%;4 CR, 12 PR), 26 pts(14.2%) had stable disease, overall yielding clinical benefit in 23%. Patients with stage IIIc, M1a and M1b were more likely to benefit (52% Vs 23% of the group, p<0.001) as well as patients previously treated by immunotherapy (p=0.026). Median OS was 9.2 months with 1 year survival of 42%. 34 pts (18.6%) are alive beyond 20 months, the majority of them received no further treatment. Factors favoring survival included stage IIIc, M1a and M1b, LDH below ULN and lymphocyte count at week 6 above 1000/ml (p values: <0.001,<0.001, 0.03 respectively). None of the 14 ocular melanoma pts exhibited clinical benefit. Conclusions: Our cohort reflects rapid adoption of this new modality. Ipilimumab had significant clinical benefit, comparable with previous reports, in a heterogenous group of patients, including those with poor prognostic factors.

Everolimus in patients with metastatic renal cell carcinoma (mRCC) who are intolerant of or have progressed after prior vascular endothelial growth factor receptor–tyrosine kinase inhibitor (VEGFr-TKI) therapy: An international expanded access program (EAP).

314 Background: The mammalian target of rapamycin (mTOR) inhibitor everolimus is the first agent to show efficacy in a randomized, controlled phase III trial in patients with mRCC after progression on VEGFr-TKIs (RECORD-1). Progression-free survival (PFS) was significantly improved (4.9 vs 1.9 months) and the risk of disease progression was reduced by 67% with everolimus compared with placebo. To fulfill an unmet medical need, everolimus was offered globally in this EAP. Presented here are preliminary results on 605 patients. Methods: The program began in July 2008 (ClinicalTrials.gov: NCT00655252 ; EudraCT: 2007-005460-28), and since then over 1,000 patients in 34 countries have been enrolled. Patients with clear cell and non–clear cell mRCC who failed or became intolerant of VEGFr-TKIs received daily oral doses of everolimus with investigator assessment every 3 months. Results: Data were collected for 605 patients who had discontinued treatment as of January 15, 2010. Evaluable patients had a mean age of 63 years, and most (94%) had progressed after prior VEGFr-TKI therapy. The adverse event (AE) profile did not differ significantly from that reported in the RECORD-1 trial. Most frequently reported grade 3–4 AEs were anemia (6.1%), stomatitis (4.6%), fatigue (4.6%), hyperglycemia (4.0%), and infection (3.6%). Grade 3–4 noninfectious pneumonitis was reported in 2.8%. Best overall response was stable disease, which was evident in 42% of patients. Conclusions: The EAP has allowed patients with mRCC access to everolimus before marketing approval. The rapid enrollment rate of this EAP confirms the unmet medical need after failure of VEGFr-TKIs. Everolimus has shown good tolerability, and no new safety issues have been identified. The investigator-assessed response rate is consistent with that reported in the RECORD-1 trial. The EAP provides an efficient framework for the development of other programs for innovative anticancer agents in patients without satisfactory therapeutic options. [Table: see text]

Pemetrexed in the treatment of malignant mesothelioma: Results from an expanded access program in Germany

An international expanded access program was initiated to provide access to treatment with pemetrexed prior registration and reimbursement for malignant mesothelioma (MM). Chemonaïve and pretreated patients with inoperable MM of the pleura or peritoneum were eligible. This report describes the results obtained in German centers. Investigators could choose between three treatments: Pemetrexed 500 mg/m(2) alone (P) or in combination with cisplatin 75 mg/m(2) (PC) or carboplatin AUC 5 (PCb). From November 2002 to June 2004, a total of 567 patients (554 with pleural MM; 41% pretreated) were included. Of 548 evaluable patients with pleural MM, 191 received P, 137 PC and 220 PCb. Patients in the P group were more often pretreated (70%) and had worse performance status compared with the other groups. In the P, PC, and PCb groups overall response rate (ORR) was 16%, 24% and 18%, median time to progression (TTP) was 5.5, 8.2, and 6.9 months, and median overall survival (OS) was 8.7, 11.3 and 9.7 months respectively. Efficacy outcomes were better for chemonaïve than for pretreated patients, and P was less hematotoxic than PC or PCb. Treatment of pleural MM with pemetrexed alone or in combination with platinum was safe and active as first and second-line therapy.

7154 An International Expanded Access Program (EAP) of RAD001 (everolimus) in patients with metastatic renal cell carcinoma (mRCC) who fail, or become intolerant of a prior vascular endothelial growth factor receptor (VEGFr) therapy

7154 An International Expanded Access Program (EAP) of RAD001 (everolimus) in patients with metastatic renal cell carcinoma (mRCC) who fail, or become intolerant of a prior vascular endothelial growth factor receptor (VEGFr) therapy

Pemetrexed Plus Cisplatin or Pemetrexed Plus Carboplatin for Chemonaïve Patients with Malignant Pleural Mesothelioma: Results of the International Expanded Access Program

Previously published results from a randomized phase III study of pemetrexed plus cisplatin in patients with malignant pleural mesothelioma (MPM) demonstrated a significant survival benefit and higher response rate compared with cisplatin. Although pemetrexed was under review by regulatory agencies, an International Expanded Access Program (EAP) provided more than 3000 mesothelioma patients with access to single-agent pemetrexed or pemetrexed in combination with cisplatin or carboplatin in 13 countries. This manuscript reports the safety and efficacy data from the nonrandomized open-label study in chemonaïve patients receiving pemetrexed plus platinum under the EAP. Patients with histologically confirmed MPM, not amenable to curative surgery, received pemetrexed 500 mg/m in combination with either cisplatin 75 mg/m or carboplatin AUC 5, once every 21 days with standard premedication. Efficacy data were recorded at the end of study participation. A total of 1704 chemonaïve patients received pemetrexed plus cisplatin (n = 843) or pemetrexed plus carboplatin (n = 861) and were evaluated for safety. The efficacy evaluable population consisted of 745 patients in the pemetrexed plus cisplatin group and 752 patients in the pemetrexed plus carboplatin group for whom physician-reported tumor response was available. The pemetrexed plus cisplatin group demonstrated a response rate of 26.3% compared with 21.7% for the pemetrexed plus carboplatin group, with similar 1-year survival rates (63.1% versus 64.0%) and median time to progressive disease (7 months versus 6.9 months). The most common grade 3/4 hematologic toxicity was neutropenia in 23.9% of the pemetrexed plus cisplatin group and 36.1% of the pemetrexed plus carboplatin group. This large EAP confirmed the activity of pemetrexed plus cisplatin and pemetrexed plus carboplatin in chemonaïve patients with MPM, demonstrating clinically similar time to progressive disease and 1-year survival rates.

Single-Agent Pemetrexed for Chemonaïve and Pretreated Patients with Malignant Pleural Mesothelioma: Results of an International Expanded Access Program

Pemetrexed has established efficacy, and is the backbone for chemotherapy in patients with malignant pleural mesothelioma (MPM). An International Expanded Access Program provided >3000 mesothelioma patients with access to single-agent pemetrexed or pemetrexed plus platinum analogs (cisplatin or carboplatin) in 13 countries. In this article, we report the safety and efficacy data of MPM patients who were treated with single-agent pemetrexed (n = 812). Patients with histologically confirmed MPM, not amenable to curative surgery, received pemetrexed (500 mg/m) once (day 1) every 21 days with standard premedication and vitamin supplementation. Investigator-determined response and survival data were recorded at the end of study participation. Myelosuppression data were also collected. All 812 MPM patients (319 chemonaïve; 493 pretreated) received single-agent pemetrexed (>or=1 dose) and were evaluated for safety. A total of 643 patients (247 chemonaïve, 396 pretreated) were evaluated for efficacy. Of the chemonaïve patients evaluated for efficacy (n = 247), the overall response rate was 10.5%, median time to progressive disease (TTPD) was 6.0 months, and median survival was 14.1 month. Of the pretreated patients evaluated for efficacy (n = 396), the overall response rate was 12.1%, median TTPD was 4.9 months, and the median survival was not estimable due to high censoring. Common terminology criteria grade 3/4 hematologic toxicity was mild in both groups, with neutropenia (<18%) as the main toxicity. In the present expanded access program, single-agent pemetrexed demonstrated promising activity in MPM in both chemonaïve and pretreated patients, with TTPD of 6.0 and 4.9 months, respectively, 1-year survival >or=54.7%, and mild hematologic toxicity.

Report of an international expanded access program of imatinib in adults with Philadelphia chromosome positive leukemias

BackgroundImatinib is a selective inhibitor of the BCR/ABL tyrosine kinase. The remarkable initial results of the first phase I clinical trial published in 1999 prompted the rapid initiation of large phase II trials. They also generated intense media coverage and significant interest from patients and clinicians and demand for access to imatinib before marketing approval. In response, a worldwide expanded access program (EAP) for imatinib was implemented in May 2000. PatientsIn total, 7380 patients with chronic myeloid leukemia (CML) and acute lymphoblastic leukemia failing prior therapies were enrolled in 106 centers in 34 countries. ResultsTime to progression and overall survival, as well as the safety profile, were similar to those observed in published phase II studies. At the end of the program, patients benefiting from treatment were continued on imatinib therapy by transferring to national health care systems or patient assistance programs. ConclusionThe imatinib EAP successfully provided therapy to patients with CML before marketing approval. The program provides an efficient framework for the development of global EAPs for innovative investigational anticancer agents in patients without a satisfactory therapeutic alternative.

Pemetrexed (P) alone or in combination with platinum for malignant pleural mesothelioma (MPM): Efficacy and toxicity of the International Expanded Access Program (EAP) in Spanish patients (p)

19038 Background: A landmark phase III study reported a significant survival benefit for P+cisplatin (cis) versus cis alone in MPM (Vogelzang et al. JCO 2003). EAP provided access to P alone or P plus a platinum for 3311 MPM p in 13 countries. Safety and efficacy data for Spanish p are summarized in this abstract. Methods: From Feb 2003 to May 2005, 225 advanced MPM p were enrolled at 26 sites in Spain. P 500 mg/m2 was given alone or in combination with either cis 75 mg/m2 or carboplatin (Cb) AUC 5 once every 21 days with standard pre-medication (vitamin B12, folic acid, and dexamethasone). Results: 221 MPM p were evaluable for safety and 180 (113 chemonaïve; 67 pre-treated) for efficacy. Median age, 60 yrs (range: 25–89); 78.7% male; 73.3%, Karnofsky score ≥80. Response rate: 27% in the P group, 27.5% in the P+cis group and 30.4% in the P+Cb group, with a clinical benefit rate of 51.4%, 65.5% and 78.6%, respectively. Median time to progression (TTP): 6.9 months (m) in the P group and 8 m in the P+cis group. Median survival (MS): 14.1 m in the P group and 13.4 m in the P+cis group (figure). Neither TTP nor MS could be estimated in the P+Cb group due to high censoring rate. 1-year survival: 67.2% for the P group, 57.1% for the P+cis group, and 62.8% for the P+Cb group. Hematological toxicity was tolerable. Conclusions: Treatment with P plus a platinum resulted in improved survival in MPM compared to cis or Cb alone, with a manageable toxicity, supporting the findings of the phase III study. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Lilly Oncology

6571 POSTER Open-label study of pemetrexed (P) alone or in combination with a platinum in patients (pts) with peritoneal mesothelioma (PM): results from the international expanded access program (EAP)

6571 POSTER Open-label study of pemetrexed (P) alone or in combination with a platinum in patients (pts) with peritoneal mesothelioma (PM): results from the international expanded access program (EAP)

C5-01: Open-label study of pemetrexed alone or in combination with a platinum in chemonaïve patients (pts) with malignant pleural mesothelioma (MPM): Results from the International Expanded Access Program (EAP)

C5-01: Open-label study of pemetrexed alone or in combination with a platinum in chemonaïve patients (pts) with malignant pleural mesothelioma (MPM): Results from the International Expanded Access Program (EAP)

C5-03: Open-label study of pemetrexed alone or in combination with a platinum for previously treated patients (pts) with malignant pleural mesothelioma (MPM): Outcomes from the International Expanded Access Program (EAP)

C5-03: Open-label study of pemetrexed alone or in combination with a platinum for previously treated patients (pts) with malignant pleural mesothelioma (MPM): Outcomes from the International Expanded Access Program (EAP)

Open-label study of pemetrexed alone for chemonaive patients and pre-treated patients with malignant pleural mesothelioma: Outcomes of the International Expanded Access Program (EAP)

7709 Background: In a previous phase II study of chemonaive malignant pleural mesothelioma (MPM) patients (pts), single-agent pemetrexed (P) resulted in a 14.1% response rate (RR) and median survival of 10.7 mos (95% CI 7.7–14.5) (Scagliotti 2003). Likewise, the P arm in a phase III study of pre-treated MPM pts yielded an 18.7% RR (40.7% with stable disease, SD) and median survival of 8.4 mos (95% CI 6.2–10.5) (Jassem 2006). The EAP provided 3311 MPM pts with access to P alone, P plus cisplatin, or P plus carboplatin in 13 countries. In this abstract we report on the safety and efficacy data of those MPM pts treated with P alone. Methods: Eligible pts had histologic or cytologic diagnosis of MPM and were either chemonaïve or previously treated with =1 line(s) of chemotherapy. Pts pre-treated with P were allowed if they had experienced clinical benefit from the prior P. Treatment consisted of P (500 mg/m2) once (day 1) every 21 days with standard pre-medication of vitamin B12, folic acid, and dexamethasone. Investigator-determined response (RR) and survival data (with censoring) were recorded at the end of study participation. Myelosuppression data (CTC) were also collected. Results: 812 MPM pts (319 chemonaïve; 493 pre-treated) received =1 dose of P and were evaluated for safety, and 643 pts (247 chemonaïve; 396 pre-treated) were evaluated for efficacy (RR and survival). In chemonaïve pts with MPM, the median age was 69 yrs (range: 39–87 yrs), 78.1% were male, and 71.6% had a KPS ≥80 (of the 93% who had PS evaluated). In pre-treated pts with MPM, the median age was 63 yrs (range: 31–85 yrs), 75.9% were male, and 74.5% had a KPS ≥80 (of the 95% who had PS evaluated). Both groups received a median of 4 cycles (chemonaive group range 1–18; pretreated group range 1–23). See the table for efficacy and safety data. Conclusions: Results of the EAP confirm earlier phase II and phase III studies. No significant financial relationships to disclose. [Table: see text]