Olaparib in the maintenance treatment of platinum-sensitive relapse of BRCA mutant ovarian cancer in routine clinical practice: first results of observational study in Russian patients

Background and aims. There is no data on olaparib efficacy and safety in Russian routine clinical practice. Methods. We analysed the 30 consecutive patients who received maintenance olaparib treatment for platinum-sensitive relapse (PSR) of ovarian or fallopian tube cancer in Russian Cancer Centers. Patients were prescribed olaparib capsules 400 mg twice daily. Radiographic assessments were done every 8 weeks. Patient characteristics. Age median 55 (range 39-68); 26 (86,6%) patients had gBRCA1, 2 (6,6%) patients had sBRCA1, 2 (6,6%) patients had gBRCA2. Number of relapse: median 1 (range 1-10), number of lines of chemotherapy: median 2 (range 2-11). Last regimen of chemotherapy: taxane + platinum (± bevacizumab) 90% (27/30), platinum monotherapy 10% (3/30). Best response to the last chemotherapy complete response 43,3% (13/30), partial response 36,7% (11/30), stable disease 20% (6/30). Results. Median follow-up in 13 CR patients was 12 mos. 1 CR patient progressed after 9 mos of maintenance olaparib. Median follow-up in 11 PR patients was 7 mos. 3 PR patients achieved CR on olaparib. 1 PR patient progressed after 6 mos of olaparib maintenance. Median follow-up in SD patients was 12 mos. 1 SD patient achieved PR on olaparib, there were no progressions. 10 (30%) patients had adverse events (AEs). 1 patient had grade 3 AE and 2 patients had AEs leading to dose reduction. There were no grade 4 AEs. Conclusions. Olaparib is safe and effective maintenance treatment of PSR ovarian cancer in routine clinical settings.

Veliparib Monotherapy to Patients With BRCA Germ Line Mutation and Platinum-Resistant or Partially Platinum-Sensitive Relapse of Epithelial Ovarian Cancer: A Phase I/II Study

ObjectiveA new treatment principle, which seems to radically change the treatment approach in ovarian cancer (OC), has developed over the past few years. Poly(ADP-ribose) polymerase inhibitors work by interfering with mechanisms important to DNA damage repair. Cancer cells that already have defects in the BRCA genes are particularly sensitive to treatment with poly(ADP-ribose) polymerase inhibitors. The main purpose of this study was to investigate the effect of veliparib in patients with known BRCA1/2 mutations and with a platinum-resistant or intermediate sensitive relapse of OC.MethodsMajor eligibility criteria were primary epithelial ovarian/fallopian/peritoneal cancer patients with a platinum-resistant or intermediate sensitive relapse of OC and with evaluable disease by either Response Evaluation Criteria In Solid Tumors or Gynecological Cancer Intergroup CA-125 criteria. Patients were treated with oral veliparib twice daily on days 1 to 28.ResultsSixteen patients were enrolled in the phase I part, and a maximum tolerable dose of 300 mg twice daily was established. The phase II part enrolled 32 patients with a median of 4 previous treatment regimens. The overall response rate combining Response Evaluation Criteria In Solid Tumors and CA-125 response was 65% (6% complete response and 59% partial response). Progression-free and overall survival rates of the intention-to-treat population were 5.6 months (95% confidence interval, 5.2–7.3 months) and 13.7 months (95% confidence interval, 10.2–17.3 months), respectively. The most common phase II treatment-related grade 2 toxicities included fatigue (22%), nausea (22%), and vomiting (9%).ConclusionsTreatment with veliparib in heavily pretreated patients with relapse of OC demonstrates a considerable efficacy with an acceptable toxicity profile.

Allogeneic Stem-Sell Transplantation In Multiple Myeloma In Real Practice: Long-Term Results From a Single Institution

Background Allogeneic stem-cell transplantation with myeloablative conditioning (MAC) in multiple myeloma (MM) is associated with a high transplant-related mortality (TRM) with a 15% of long-term survivors. Allogeneic transplantation with reduced-intensity conditioning (alloRIC) results in a lower TRM with a higher relapse rate. When used in first line in a tandem transplant approach (auto/alloRIC), the incidence of acute graft-versus host disease (aGvHD) grade II-IV reported ranges between 20-43%, chronic GvHD between 50-75% and the TRM between 10-15%. The reported PFS was 25% beyond 7 years. Because of this high morbimortality and the higher rate of relapse, the role of allogeneic transplantation in MM remains controversial, especially as part of the front-lline therapy. Aim to analyze the results of allogeneic transplantation in patients with MM outside clinical trials at our institution over a period of 27 years. Patients and Methods Between Feb 1986 and April 2009, 23 patients (17 M, 6 F, median age 41 –range 21-52 -) received a MAC from an HLA identical sibling donor. Disease status at the time of transplant was first response in 12 patients (53%) (3 CR, 9 PR), sensitive relapse in 3 (13%) (all PR) and refractory disease in 8 (35%). Conditioning regimen was heterogeneous (6 Cyclo/TBI, 2 Bu/Cyclo, 3 BCNU/Mel/Cyclo/TBI, 4 Cyclo/Mel/TBI, 5 Mel/TBI, 2 Bu/Mel). GvHD prophylaxis consisted on cyclosporine/MTX (10), cyclosporine/PDN (8), cyclosporine (2) or other (3). Between April 2001 and Aug 2012, 31 patients (18 M, 13F, median age 48 –range 25-64) received an alloRIC: 25 of them (80%) from an identical sibling donor and 6 (20%) from an unrelated donor. Seven patients (13%) who did not achieve a CR after front-line autologous transplant received an alloRIC in a tandem strategy. 17 (31%) were in sensitive relapse (first relapse 14, second relapse 3). Seven patients (13%) had refractory disease at the time of alloRIC. Conditioning regimen consisted on Fluda/Mel (26 patients), Flu/TBI (3) and Fluda/Mel/bortezomib (2). GVHD prophylaxis consisted on cyclosporine/MTX (6) or cyclosporine/MMF (25). All patients in the alloRIC group had received a prior single autologous transplant. Results On an intention-to-treat analysis, the CR rate after MAC was 35%. The incidence of aGvHD grade II-IV and III-IV were 48% and 39%, respectively. The TRM at any time was 56%. The causes of death were GvHD in 7 patients, infection not related to GvHD in 5 patients and VOD in 1 patient. The relapse rate was 30%.There are 3 patients who remain in continued CR at 13, 23 and 27 years beyond transplantation. With alloRIC the CR rate was 45%. The incidence of aGvHD grade II-IV and III-IV were 55% and 22%, respectively. Nine patients develop chronic GvHD. The TRM at any time was 29% and the causes of death were GVHD in 7 patients and pulmonary hemorrhage and postransplant lymphoma one patient each. Nine patients remain alive in continued CR from 5 months to 9 years of follow-up. After a median follow-up of 36.4 months, the median PFS was not significantly different between MAC and alloRIC and there was a trend towards a longer overall survival in the alloRIC group (4.6 vs 35 months, p=0.05). Conclusions Although a small fraction of patients with MM can be cured with MAC allogeneic transplantation, this procedure is associated with an extremely high TRM. Unfortunately, alloRIC was also associated with a high incidence of severe aGVHD resulting in a high TRM leading to a short PFS. New approaches aimed at decreasing the incidence of aGVHD are crucial. Disclosures: Jiménez: Janssen: Honoraria. Rosiñol:Janssen: Honoraria; Celgene: Honoraria. Blade:Janssen: Honoraria; Celgene: Honoraria.

Efficacy of rechallenge chemotherapy in patients with sensitive relapsed small cell lung cancer.

7088 Background: Treatment efficacy of rechallenge chemotherapy recommended for patients with sensitive-relapse small cell lung cancer (SCLC) has not been fully clarified. Methods: We defined sensitive relapse as treatment-free interval (TFI) ≥ 90 days. Sixty-five sensitive-relapse SCLC patients who received second-line chemotherapy at the Shizuoka Cancer Center between September 2002 and May 2011 were separated into those treated with rechallenge chemotherapy (rechallenge group) and those treated with other regimens (other group) for comparison and analysis of treatment efficacy. Results: No significant differences in age, gender, ECOG performance status at relapse, disease extent at diagnosis, or response to first-line treatment were found between the two groups, but TFI was significantly longer in the rechallenge group, which included 19 sensitive-relapse patients. The other group included 46 sensitive-relapse patients, 21 of whom received amrubicin. There was no significant difference in overall survival (OS) between the two groups (median survival time (MST): rechallenge group 14.4 months, other group 13.1 months, p = 0.51). In the patients treated with amrubicin, MST was 12.6 months. Comparing the rechallenge group with the patients treated with amrubicin, there was also no significant difference in OS (p = 0.38). Both the rechallenge and other group included 11 patients with ex-sensitive relapse (TFI ≥ 180 days). There was no significant difference in OS between the two groups (MST 15.7 vs. 26.9 months, p = 0.46). Conclusions: Rechallenge chemotherapy did not prove superior to other chemotherapies, suggesting that monotherapy, such as amrubicin, might be reasonable as second-line chemotherapy for sensitive-relapse SCLC patients.

High-Dose Therapy (HDT) with Hematopoietic Stem Cell Transplantation (HSCT) Is Effective Therapy for Patients with Non-Hodgkin Lymphoma (NHL) and Central Nervous System (CNS) Involvement

Abstract 1358 Patients with NHL and CNS involvement have a poor prognosis when treated with conventional therapy. We performed a retrospective review of the Nebraska Lymphoma Study Group database to identify patients with NHL and CNS involvement who underwent HSCT. CNS involvement was defined as the presence of lymphomatous cells in cerebrospinal fluid, clear evidence of leptomeningeal disease by imaging studies, or biopsy proven parenchymal disease. Between January 1991 and December 2006, 24 such patients underwent HDT/HSCT. The median age at transplantation was 43 years (range 20–61). Fifty four percent of patients had diffuse large B-cell lymphoma. Sixty three percent of patients had parenchymal CNS involvement. CNS directed therapy as part of salvage prior to transplantation included intrathecal chemotherapy in 19 patients, high-dose methotrexate in 15 patients, and cranial irradiation in 10 patients. All but one patient achieved CNS remission prior to transplant. Twenty patients underwent autologous HSCT and four underwent allogeneic HSCT. The majority of patients were conditioned with carmustine, etoposide, cytarabine and melphalan (BEAM). At a median follow-up of 67 months for surviving patients (range 35–224 mo) the 1-year progression-free survival (PFS) is 50% (95% confidence interval [CI] 30–67) and the 5-year PFS is 38% (95% CI 20–56). The 1-year overall survival (OS) is 65% (95% CI 44–80) and the 5-year overall survival is 52% (95% CI 31–70). Eleven patients have relapsed and all relapses occurred within 13 months of HSCT. Thirteen patients remain alive and in remission. There have been 9 deaths due to disease recurrence and one death with no evidence of relapse. Among 15 patients who received high-dose methotrexate as part of CNS directed therapy the 5-year probability of PFS was 47% (95% CI 23–68) compared with 22% (95% CI, 3–51) in 9 patients not receiving high-dose methotrexate (p = 0.24). For patients transplanted as consolidation of initial therapy (n = 9) the 3-year probability of PFS was 63% (95% CI 29–96) compared with 36% (95% CI 0–71) for 12 patients transplanted in sensitive relapse (p = 0.36). Those same 9 patients had an 88% probability of survival at three years post transplant (95% CI 65%-100%) compared with 33% (95% CI 0–68) for the 12 patients with sensitive relapse (p = 0.046). In conclusion patients with NHL and CNS involvement who undergo HDT/HSCT appear to have similar outcomes to patients transplanted without CNS involvement. Patients destined to relapse appear to do so relatively soon after transplantation. Patients who received high-dose methotrexate as CNS directed therapy prior to transplant had a trend toward superior PFS compared with those receiving only intrathecal methotrexate, CNS irradiation, or both. Disclosures: No relevant conflicts of interest to declare.

An open label phase II trial of the Plk1 inhibitor BI 2536, in patients with sensitive relapse small cell lung cancer (SCLC)

8108 Background: BI 2536 is a potent, selective inhibitor of polo-like kinase 1 (Plk1), a regulator of mitotic progression. BI 2536 demonstrated favorable tolerability and antitumor activity in phase I trials. We investigated the antitumor efficacy, safety and PK of BI 2536 in patients (pts) with sensitive relapse SCLC. Methods: This open label single arm phase II study followed a Gehan two-stage design. Primary objective was to determine the antitumor efficacy of BI 2536 in SCLC pts with disease recurrence ≥60 days after completion of first-line chemotherapy. 18 pts had to complete 2 courses to be evaluable for stage 1 analysis. In case of ≥2 partial or complete antitumor responses (RECIST criteria), stage 2 accrual would continue until 40 pts were entered. Patients received 200 mg BI 2536 as a 1h i.v. infusion on Day 1 every 3 weeks. Dose escalation to 250 mg (cycle 3 onwards) was encouraged in pts with <Grade 2 drug related non-hematologic and <Grade 3 hematologic toxicity. Results: 23 pts (14 female, 9 male, 21 extensive disease, 2 limited disease), median age 60 yrs (range: 35–77) were treated. All patients had disease recurrence >60 days after completion of first-line therapy. Of 23 pts, no objective antitumor responses were observed, 7 had stable disease as best response, 14 had progression, 2 were not evaluable. A median of 2 courses were given, up to a maximum of 12 in 1 pt. The PFS rate at 3 months was 25%. Due to the lack of antitumor responses, trial accrual was terminated after stage 1. Overall, BI 2536 was well tolerated. Frequent AEs were neutropenia (48%), fatigue (39%), nausea (30%), anemia, vomiting, constipation (26% each), and thrombocytopenia (22%). Drug related grade 3/4 AEs were neutropenia (13%/26%), grade 3/4 thrombocytopenia (1 pt each), grade 3/4 anemia (1 pt each), grade 4 sepsis (1 pt), Grade 4 ARDS (1 pt) and Grade 3 fatigue (1 pt). PK analyses indicate that BI 2536 has high clearance (>1,000 mL/min) and quickly distributes in multiple compartments in a large volume of distribution (>1,000 L). Estimated elimination half-life was >25 h. Conclusions: BI 2536 was well tolerated in relapsed SCLC pts, but demonstrated no convincing antitumor efficacy after stage I of the study. Therefore, BI 2536 will not be assessed further as a single agent in SCLC. [Table: see text]