Refractory Germ Cell Tumors Research Articles

Antitumor activity of brentuximab vedotin in CD30 positive refractory germ cell tumors.

327 Background: Brentuximab Vedotin (BV) is a novel antibody drug conjugate that combines the agent mono-methyl auristatin E (MMAE) to a CD-30 specific monoclonal antibody by a protease-cleavable linker. It is approved by the FDA for treatment of relapsed Hodgkin lymphoma (HL) and systemic anaplastic large cell lymphoma (ALCL). In addition to HL and ALCL, CD-30 expression has been reported on malignant tumors of non-lymphoid origin including testicular embryonal carcinoma (EC). Here we report our initial experience in three heavily pre-treated patients with CD30-positive EC who were treated as part of an ongoing phase 2 open-label multicenter study designed to evaluate the antitumor activity of BV in patients with CD30-positive non-lymphomatous malignancies. Methods: Three men with relapsed or refractory, histologically confirmed CD-30 positive testicular cancer received BV until progression or toxicity. CD-30 expression was assessed by immunohistochemistry. All 3 patients were dosed at 1.8 mg/kg IV every 21 days and followed for response at cycles 2, 4. Results: Three patients were enrolled at 2 sites in the US. Median age was 26 years (range 24-33). All 3 patients progressed after high dose chemotherapy with peripheral blood stem cell transplant. Two patients received BV as 4th line and 1 patient as 3rd line therapy. Tumor sites included lungs, liver, retroperitoneal, mediastinal and supraclavicular lymph nodes. The first patient baseline hCG was 5571. After 2 cycles of therapy, hCG nadir was 45 with a radiologic partial response (PR) by RESICT that lasted 2 months. He then had serologic and radiographic progression in the liver while on therapy. Patient 2 was serologic marker negative and had a radiographic PR by RECIST in lung and mediastinum after cycle 2 and continues on therapy. Patient 3 had a baseline hCG of 10400, with nadir at 110 after 2 doses and continues to have serologic response. By RECIST he currently has stable disease. The treatment was well tolerated in all 3 patients with no grade 3-4 toxicities. Conclusions: All 3 patients with heavily pretreated CD-30 positive EC had clinical benefit after treatment with brentuximab vedotin. The treatment was well tolerated. The enrollment is ongoing in this Phase 2 study. Clinical trial information: NCT01461538.

A phase 2 multicenter study of tivantinib (ARQ 197) monotherapy in patients with relapsed or refractory germ cell tumors

Tivantinib is a selective, small-molecule inhibitor of the MET receptor tyrosine kinase. Preclinical and phase 1 data suggested a possible role for MET in the pathophysiology of germ cell tumors (GCTs) and a potential clinical benefit from tivantinib in patients with these tumors. Men (≥ 16 years) with relapsed or refractory, histologically confirmed, non-central nervous system GCTs received oral tivantinib 360 mg twice daily in 28-day cycles until progressive disease or unacceptable toxicity. The primary endpoint was objective response rate in the first 4 cycles, with study termination for <2 responses among the first 21 patients. Secondary endpoints included 12-week progression-free survival (PFS), overall survival (OS), and safety. Twenty-seven patients were enrolled in 9 months (median age, 32 years). Most patients had tumors with nonseminoma histology (n = 25), and primary tumor sites were testis (n = 24) and mediastinum (n = 3). Among 25 evaluable patients, no objective responses were observed; accrual was halted when the 21st patient became evaluable. Best response was stable disease (n = 5). Median PFS was 1 month, the 12-week PFS rate was 21 %, and median OS was 6 months. Grade 3 or 4 adverse events considered related to study drug included grade 3 pneumonia and grade 3 syncope (n = 1, each). Tivantinib was well tolerated but did not demonstrate single-agent activity in patients with relapsed/refractory GCTs. Rapid accrual to this phase 2 trial was achieved in this rare patient population through multicenter collaboration.

Paclitaxel-Based High-Dose Chemotherapy with Autologous Stem Cell Rescue for Relapsed Germ Cell Tumor: Clinical Outcome and Quality of Life in Long-Term Survivors

BackgroundHigh-dose chemotherapy (HDCT) is a viable and potentially curative approach for patients with relapsed or refractory germ cell tumors (GCTs). However, no comparative data exist to define the optimal chemotherapeutic strategy, and little is known about the quality of life (QOL) of long-term survivors. Herein we attempt to characterize the QOL in long-term survivors who received high-dose paclitaxel, etoposide, carboplatin, and ifosfamide (TECTIC). Patients and MethodsDetails of the TECTIC regimen and clinical outcomes for the initial 33 patients have been reported. In the present study, we report the clinical data for 15 additional patients. Using the European Organization for the Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) and the Functional Assessment of Cancer Therapy–Taxane (FACT-T) questionnaires, we surveyed all patients who survived at least 4 years after HDCT. ResultsForty-eight patients were enrolled and 46 patients received protocol therapy. For all 48 patients, the median progression-free survival (PFS) and overall survival (OS) were 11.8 months (range, 5.8-not reached) and 21.7 months (range, 12.7-not reached), respectively. Seventeen patients were progression free at a median of 123.2 months (51.6-170.2 months), and 6 patients remain alive after progression with a median OS of 68.8 months (47.6-147.1 months). Of the 23 surviving patients, 18 were accessible and consented to telephone interviews. Compared with historical cohorts, survivors had a higher global health scale score (87.04 vs. 75.62; P = .02) but a lower physical functioning score (68.89 vs. 92.66; P = .0001) by the QLQ-C30 scale. ConclusionsHDCT with the TECTIC regimen produces durable remissions in patients with relapsed or refractory GCTs with acceptable QOL in long-term survivors.

WS14-5 - Management of Advanced Testicular Cancer

ABSTRACT Introduction Though eighty percent of advanced germ cell tumors (GCTs) could be cured to date, only 20–30% of patients with chemotherapy refractory or resistant GCTs, so called ‘difficult-to-treat’ GCTs would remain continuously disease-free with salvage chemotherapy or surgery. International classification gave us to the information about induction and second-line chemotherapy, however, the optimal salvage chemotherapy remains unclear. In this session, we will review literatures and present our sequential chemotherapy strategy for advanced GCTs. Patients and methods Two hundred sixteen patients with advanced GCTs treated at Kyoto Prefectural University of Medicine from June 1998 to December 2011 were retrospectively assessed. Results Median age was 32 years (range: 17–68 years). Non-seminoma was in 181 cases (83.8%), regarding primary histology. IGCCC showed good in 94 cases (45.2%), intermediate 58 (27.9%), poor 56 (26.9%). As the induction therapy, BEP therapy was carried out in 190 cases (88.0%). Salvage chemotherapy was done for 121 cases. As the second-line therapy, VIP/VeIP and TIP/N therapy were done in 42 (34.7%) and 41 cases (33.8%), respectively. Regarding the patients requiring third line or more chemotherapy, 90, 61, 39, 23 cases had third, fourth, fifth and sixth line or more chemotherapy, respectively. Irinotecan-containing chemotherapy was done in 22 cases and 35 cased as second- + third-line therapy and fourth line or more, respectively. Gemcitabine-containing therapy was done in 35 cases with fourth line or more chemotherapy. The overall survival rate at median follow-up period was 95.7% in induction chemotherapy group (median follow-up; 53 months) and 69.2% in salvage chemotherapy group (median follow-up; 47 months). Clinical outcomes showed no evidence of disease (NED) was obtained in 91.5% and 90.3% with induction and second-line therapy, respectively. Noteworthy mentioned, about 40% patients had NED even in the fourth line or more chemotherapy group. Conclusion Very good and relatively good prognosis were obtained in the patients with induction and salvage chemotherapy at high volume center, respectively. Sequential continuous chemotherapy would be very important to manage ‘difficult-to-treat’ advanced germ cell tumors.

Salvage Therapy with High-Dose Chemotherapy and Peripheral Blood Stem Cell Transplant in Patients with Primary Mediastinal Nonseminomatous Germ Cell Tumors

Salvage therapy with high-dose chemotherapy (HDCT) and bone marrow transplant (BMT) or peripheral blood stem cell transplant (PBSCT) has curative potential in patients with recurrent germ cell tumor. However, patients with primary mediastinal nonseminomatous germ cell tumors (PMNSGCTs) have had poor results with any form of salvage chemotherapy including HDCT. We switched from BMT to PBSCT in 1996. One hundred sixteen of 184 patients (63%) with recurrent or refractory germ cell tumors treated from 1996 to 2004 were alive and continuously disease-free. PMNSGCTs were excluded from that study because of poor results in the patient population with HDCT and BMTs. In 2006, we resumed treating patients with recurrent PMNSGCT with 2 consecutive courses of HDCT consisting of carboplatin 700 mg/m2 × 3 plus etoposide 750 mg/m2 × 3 and each followed by an infusion of autologous peripheral-blood hematopoietic stem cells with a second course 3 to 4 weeks later. Twelve patients were treated: 11 as initial salvage chemotherapy and 1 as fourth-line therapy. Eight of the 12 patients had major thoracic resections at the time of the relapse after initial chemotherapy. Three of the 12 patients achieved complete remission (CR; 10, 15, and 50 months' duration). One patient remains continuously with no evidence of disease (NED) at 50 months. An additional patient is currently NED at 52 months with HDCT and subsequent surgery. Median survival for the 12 patients was 11 months (range, 4-52 months). Results with tandem transplant for recurrent PMNSGCT remain poor compared to primary testis cancer, but durable CR and probable cure can be achieved in a small subset of patients with PMNSGCT. In our opinion, salvage surgical resection if anatomically feasible is the preferred option for patients with PMNSGT progressing after initial chemotherapy.

Interim results of phase II trial of the cyclin-dependent kinase 4/6 inhibitor PD-0332991 in refractory retinoblastoma protein positive germ cell tumors.

4596 Background: Deregulation of the retinoblastoma pathway in germ cell tumors (GCT) has been well documented. We previously reported that PD-0332991, a selective oral inhibitor of cyclin-dependent kinase 4/6, led to prolonged disease control in 3 patients (pts) with unresectable growing teratoma syndrome (NEJM, 2009). For these reasons, we initiated a phase II trial of PD-0332991 in pts with refractory retinoblastoma protein (Rb) positive (+) GCT. Methods: Pts with incurable refractory GCT that expressed Rb by immunohistochemistry were treated with PD-0332991 125 mg orally daily for 21 days followed by a 7 day break (cycle = 28 days). Tumor assessments were performed every 2 cycles. The primary endpoint was 6-month progression-free survival (PFS) rate. Results: As of 1/12/2012, archived tumors from 36 pts with refractory GCT were stained for Rb and 35 had ≥ 1+ staining. 18 of planned 24 pts have been enrolled and treated. Pt characteristics: 17 male, 1 female; median age, 31 years (range, 17-56); median ECOG performance status, 1 (range, 0-1); median number of prior chemotherapy regimens, 2 (range, 1-6); median number prior surgeries, 3 (range, 1-6). Pt pathology: mature teratoma (MT), 7; teratoma with malignant transformation (TMT), 7; mixed GCT, 2; late relapse (LR), 2. 16 pts are evaluable; 2 pts are too early to evaluate. 5 of 16 evaluable pts achieved 6-month PFS (3 MT, 1 TMT, 1 LR). Median PFS was 2 months (range, 0-17). No objective radiological responses were observed; 7 patients had best response of stable disease by RECIST criteria (3 MT, 3 TMT, 1 LR). Grade 3 toxicity included neutropenia (4 pts), thrombocytopenia (3 pts), anemia (1 pt), mucositis (1 pt). No grade 4 toxicity was seen. Analysis of archival tumor for predictive biomarkers including Rb and p16 expression is being performed. Conclusions: PD-0332991 has resulted in 6-month PFS in pts with refractory Rb + GCT, including pts with incurable teratomas.

Phase II study of everolimus (E) in refractory germ cell tumors (GCTs).

TPS4677 Background: GCTs represent a model for the cure of cancer. Nonetheless, a small proportion of patients (pts) develop disease recurrence. Because of insufficient results in the treatment of relapsed GCTs, evaluation of new treatments is a priority. Loss of the tumor suppressor gene PTEN (phosphatase and tensin homolog) marks the transition from intratubular germ cell neoplasias (ITGCN) to invasive GCTs. In the testis, PTEN was abundantly expressed in germ cells whereas it was virtually absent from 56% of seminomas as well as from 86% of embryonal carcinomas and virtually all teratomas. On the contrary, ITGCN intensely expressed PTEN, indicating that loss of PTEN expression is not in early event in GCTs development, but is associated with disease progression. PTEN inactivation is associated with dysregulation of PI3K/Akt pathway and increased mTOR signalling. We hypothesize that dysregulation of PI3K/Akt pathway due to PTEN inactivation in GCTs suggests that these pts could have greater benefit from mTOR inhibition. Methods: In December 2011, National Cancer Institute of Slovakia launched an one arm, two-staged phase II study aimed to evaluate the efficacy and toxicity of E in pts with refractory GCTs. The primary objective is to determine the efficacy of E in patients with refractory GCTs. Secondary objectives includes favourable response rate, time to progression and safety. The pts with radiological and/or serological proof of relapsed GCTs, who were not amenable to be cured by chemotherapy or surgery and who failed at least two platinum-based regimens or one platinum regimen in case of platinum-refractory disease or primary mediastinal non-seminomatous GCTs were eligible. All other standard inclusion and exclusion criteria for study of salvage treatment in refractory GCTs pts were applied. E will be administered at a dose of 10mg daily until progression or unacceptable toxicity. Assuming a response rate of clinical interest of ≥40%, a minimal response rate of 20%, a probability of 5% for rejecting an active drug, and a probability of 20% to further evaluate an ineffective drug, 18 pts will be enrolled into the first cohort. If &lt;4 responses will be observed, the study will be terminated, otherwise, it will be continued with a second cohort of 20 pts.

Paclitaxel-based high-dose chemotherapy (HDCT) for relapsed or refractory germ cell tumors (GCTs): Clinical outcome and quality of life (QOL) in long-term survivors.

e16563 Background: HDCT is a viable and potentially curative approach for patients with relapsed or refractory GCTs. However, no comparative data exist to define the optimal chemotherapeutic strategy. Herein, long-term follow-up data and QOL assessments are provided for an expanded cohort of patients treated with high-dose paclitaxel, etoposide, carboplatin, and ifosfamide (TECTIC). Methods: Details of the TECTIC regimen and clinical follow-up data for an initial 33 patients have been previously reported (Margolin Biol Blood Marrow Trans 2005). Surviving patients were surveyed using a modified EORTC Quality of Life Questionairre-30 (QLQ-C30) and the Functional Assessment of Cancer Therapy-Taxane (FACT-T) questionnaire; results were compared to relevant historical cohorts using a 2-sample t-test. Cardiovascular morbidity (CM) was ascertained through queries regarding use of antihypertensive (AH) or cholesterol-lowering (CL) agents, and presence/absence of diabetes mellitus (DM). Results: Forty-six patients received protocol-based therapy. Of these, 17 patients were progression-free at a median of 112.7 mos (49.5-170.2), and 6 patients remain alive following progression with a median overall survival (OS) of 64.4 mos (43.6-147.1). Median progression-free survival (PFS) and OS were 11.8 mos (95%CI 5.8-NR) and 21.7 months (95%CI 12.7-NR), respectively. Of the 23 patients still alive, 18 patients were accessible and consented to telephonic interview. As compared to historical cohorts (Rossen J Clin Oncol 2009), survivors had a higher global health scale score (87.04 v 75.62; P=0.02) but a lower physical functioning score (68.89 v 92.66; P=0.0001) by the QLQ-C30 scale. No difference in FACT-T scores were observed as compared to historical cohorts (Cella Cancer 2003). Four patients (22%) had DM. Three patients (17%) and 4 patients (22%) reported use of AH and CL agents, respectively. Conclusions: HDCT with the TECTIC regimen produces durable remissions in patients with relapsed or refractory GCTs, with acceptable QOL and CM in long-term survivors.

Phase II trial of bevacizumab (BEV)/high-dose chemotherapy (HDC) for refractory germ-cell tumors (GCT).

4533 Background: HDC is a curative therapy for relapsed GCT. However, multiple prior relapses, cisplatin refractoriness (relapse/progression (PD) within 4 weeks) or absolute refractoriness (no prior response), or very high tumor markers at relapse predict poor early event-free survival (EFS). The validated Beyer model (JCO 1996;14:2638) identifies groups with poor risk (5% EFS at 1-year post-HDC), intermediate risk (25% EFS) or good risk (≥50% EFS). Given high VEGF expression in metastatic GCT and synergy between BEV and chemotherapy, we studied concurrent BEV/HDC in refractory GCT. Methods: Eligibility includes ≥ 1st relapse/PD, poor/interm risk and no contraindications to HDC or BEV. Treatment consisted of 2 cycles of HDC with stem-cell support following BEV (5 mg/kg) 1 week before each cycle. HDC-1 consists of a novel regimen of infusional gemcitabine with docetaxel/melphalan/carboplatin (BBMT 2005;11:297). HDC-2 includes ifosfamide/carboplatin/etoposide. Target accrual is 25 pts, to distinguish a 1-yr expected EFS of 15% (median time to progression [TTP], 9 months) from 50% 1-year EFS (median TTP, 2 years). Results: 21 pts have been treated, median age 22 (range, 19-45) poor risk (N=15) or interm risk (N=6), cisplatin refractoriness (N=9) or absolute refr (N=12), median 3 prior relapses (1-4), median 3 prior regimens (2-6), PD at HDC: 11 pts. Tumor sites: lungs (N=15), liver (8), bones (5), brain (5), retroperit (15), mediast (12). Histol at Dx: embryonal ca (4), chorio (3), mixed with teratoma (14). Prior surgery for metastases: 8 pts (6 abdomen, 1 liver, 1 brain). Prior radiation: 6 pts. Toxicity of HDC-1: grade 3 mucositis in all pts, rash (8 G2, 2 G3) and transaminase elevation; 2 pts with marginal baseline renal function died from early sepsis; 1 pt died from late fungal pneumonia. After HDC-1, markers normalized in 14/17 evaluable pts. 15 pts received HDC-2 at a median 49 (38-66) days after 1st stem cell infusion, which was well tolerated. 8 pts had residual lesions resected with findings of either teratoma (N=2) or no viable tumor (N=6). With median follow-up of 23 (3-43) months, 14 pts are alive in CR (67% EFS). Conclusions: BEV with HDCx2 shows encouraging preliminary results in heavily pretreated refractory GCT.

Paclitaxel-based high-dose chemotherapy (HDCT) for relapsed or refractory germ cell tumors (GCTs): Clinical outcome and quality of life (QOL) in long-term survivors.

325 Background: HDCT is a viable and potentially curative approach for patients with relapsed or refractory GCTs. However, no comparative data exist to define the optimal chemotherapeutic strategy. Herein, long-term follow-up data and QOL assessments are provided for an expanded cohort of patients treated with high-dose paclitaxel, etoposide, carboplatin, and ifosfamide (TECTIC). Methods: Details of the TECTIC regimen and clinical follow-up data for an initial 33 patients have been previously reported (Margolin Biol Blood Marrow Trans 2005). Surviving patients were surveyed using a modified EORTC Quality of Life Questionnaire-30 (QLQ-C30) and the Functional Assessment of Cancer Therapy-Taxane (FACT-T) questionnaire; results were compared to relevant historical cohorts using a 2-sample t-test. Cardiovascular morbidity (CM) was ascertained through queries regarding use of antihypertensive (AH) or cholesterol-lowering (CL) agents, and presence/absence of diabetes mellitus (DM). Results: Forty-six patients received protocol-based therapy. Of these, 17 patients were progression-free at a median of 112.7 mos (49.5-170.2), and 6 patients remain alive following progression with a median overall survival (OS) of 64.4 mos (43.6-147.1). Median progression-free survival (PFS) and OS were 11.8 mos (95%CI 5.8-NR) and 21.7 months (95%CI 12.7-NR), respectively. Of the 23 patients still alive, 18 patients were accessible and consented to telephonic interview. As compared to historical cohorts (Rossen J Clin Oncol 2009), survivors had a higher global health scale score (87.04 v 75.62; P=0.02) but a lower physical functioning score (68.89 v 92.66; P=0.0001) by the QLQ-C30 scale. No difference in FACT-T scores were observed as compared to historical cohorts (Cella Cancer 2003). Four patients (22%) had DM. Three patients (17%) and 4 patients (22%) reported use of AH and CL agents, respectively. Conclusions: HDCT with the TECTIC regimen produces durable remissions in patients with relapsed or refractory GCTs, with acceptable QOL and CM in long-term survivors.

Combination of paclitaxel, cisplatin, and gemcitabine (TPG) as third- to fourth-line therapy for male germ cell tumors (GCT).

341 Background: Rescue of patients (pts) who fail to be cured following 2–3 chemotherapy (CT) combinations ± high dose CT (HDCT) or who are cisplatin-refractory is still an unmet need. The identification of novel active agents/combinations is a priority. Methods: We reviewed the characteristics of consecutive pts who received TPG combination at our Institution for relapse/progression after 2 or 3 previous platinum-based CT lines. Treatment consisted of the administration of paclitaxel 80 mg/m2 IV, cisplatin 50 mg/m2 IV and gemcitabine 800 mg/m2 IV on days 1 and 8 q3w. Program provided up to 8 administrations of TPG followed by surgery of all resectable masses. Paraffin slides of all cases with residual viable cancer after TPG were retrieved: CD30 staining and somatic mutation analysis by Sequenom OncoCarta Panel v.1.0 were planned. Results: From 04/1999 to 07/2011, 74 pts have been treated with TPG, 64 in 3rd and 10 pts in 4th line. Median age was 32 (20–55), median number of prior CDDP cycles was 7 (4–10), 10 pts (13%) had already received HDCT, 4 pts had primary mediastinal GCT, 42 (57%) were CDDP-refractory/abs refractory, 25 pts (34%) had either liver, bone or brain metastases before TPG. 40% developed G3-4 hematologic and 2 pts G3 renal toxicity, none of them being dose-limiting. No treatment delays have been observed. Median number of administrations was 7 (1–10). 8 complete responses (CR), 28 partial responses with normal markers (PRm-) and 13 incomplete response/stable disease have been recorded, for a major response rate (CR+PRm-) of 49%. 34 pts (46%) underwent post-CT surgery which was radical in 15 cases (44%) and led to 7 pathologic CR. 3-, 6- and 12-month PFS was 68% (95% CI 55–76%), 31% (21–42) and 20% (12–30), respectively. 1-yr PFS after HDCT only was 24% (4–53). 12- and 24-month OS was 46% (34–57) and 26% (16–37), respectively. Median PFS and OS were 5 (1–104) and 12 mos (1–116). Conclusions: TPG combination rates first among salvage therapies for refractory GCT, even after failure of HDCT. Benchmark survival endpoints for trials on new agents/combinations have been set. Results of the biomarker analysis will be available in Feb 2012 and may help to corroborate a window of opportunity for targeted agents in GCT.

Sequential Versus Single High-Dose Chemotherapy in Patients With Relapsed or Refractory Germ Cell Tumors: Long-Term Results of a Prospective Randomized Trial

To evaluate the long-term survival rates in patients with relapsed or refractory germ cell tumors (GCTs) after single or sequential high-dose chemotherapy (HDCT). Between November 1999 and November 2004, 211 patients with relapsed or refractory GCT were randomly assigned to treatment with either one cycle of cisplatin 100 mg/m(2), etoposide 375 mg/m(2), and ifosfamide 6 g/m(2) (VIP) plus three cycles of high-dose carboplatin 1,500 mg/m(2) and etoposide 1,500 mg/m(2) (CE, arm A) or three cycles of VIP plus one cycle of high-dose carboplatin 2,200 mg/m(2), etoposide 1,800 mg/m(2), and cyclophosphamide 6,400 mg/m(2) (CEC, arm B) followed by autologous stem-cell reinfusion. Long-term progression-free survival (PFS) and overall survival (OS) 6 years after random assignment of the last patient were compared by using the log-rank test. Overall, 108 and 103 patients were randomly assigned to arms A and B, respectivelyl. The study was stopped prematurely because of excess treatment-related mortality in arm B (14%) compared with that in arm A (4%; P = .01). As of December 2010, nine (5%) of 211 patients were lost to follow-up; 94 (45%) of 211 are alive and 88 (94%) of 94 patients are progression free. Five-year PFS is 47% (95% CI, 37% to 56%) in arm A and 45% (95% CI, 35% to 55%) in arm B (hazard ratio [HR], 1.16; 95% CI, 0.79 to 1.70; P = .454). Five-year OS is 49% (95% CI, 40% to 59%) in arm A and 39% (95% CI, 30% to 49%) in arm B (HR, 1.42; 95% CI, 0.99 to 2.05; P = .057). Patients with relapsed or refractory GCT achieve durable long-term survival after single as well as sequential HDCT. Fewer early deaths related to toxicity translated into superior long-term OS after sequential HDCT.

UP-03.111 TIN Therapy as Salvage Chemotherapy for Cisplatin Refractory Germ Cell Tumors

The aim of this study was to investigate the efficacy and safeness of paclitaxel (PTX) in combination with ifosphamide (IFM) and nedaplatin (CDGP)(TIN therapy) as salvage chemotherapy for CDDP refractory GCT.

Salvage Chemotherapy with Paclitaxel, Ifosfamide, and Cisplatin (TIP) in Relapsed or Cisplatin-Refractory Germ Cell Tumors

Background: In relapsed germ cell tumors, salvage chemotherapy with paclitaxel, ifosfamide, and cisplatin (TIP) is a well-established regimen for patients with favorable features such as a primary testicular tumor and prior complete remission (CR) after the initial chemotherapy. We reviewed patients who had received salvage TIP chemotherapy, and evaluated the efficacy of TIP, linking it to patient characteristics. Patients and Methods: Between August 1998 and May 2009, a total of 14 patients were treated with salvage TIP chemotherapy. 10 of 14 had cisplatin-refractory disease, and none of the patients were expected to show a favorable outcome to conventionaldose salvage chemotherapy. Results: Of the 14 patients, 5 (37.5%) showed a favorable response (CR in 1 patient, partial response (PR) in 4 patients) to TIP alone, and 1 had CR with subsequent surgery after TIP. 2 patients with CR and another 2 patients who attained disease stabilization are still alive at 81.3, 25.4, 69.3, and 27.4 months, respectively. After a median follow-up of 41.0 months (range 11.1–137.6), the median overall survival time for all patients was 21.1 (range 5.0–112.6). Conclusions: Even in the presence of poor prognostic features, salvage TIP chemotherapy can be an active regimen in patients with relapsed or refractory germ cell tumors.

Progression‐free and overall survival in patients with relapsed/refractory germ cell tumors treated with single‐agent chemotherapy: Endpoints for clinical trial design

Refractory germ cell tumor (GCT) patients have a poor prognosis and limited treatment options. The identification of novel active agents may be impaired by use of response as the primary endpoint in phase 2 trials. Improved endpoints could enhance the development of new effective agents. The characteristics and outcome of refractory GCT patients enrolled in 7 single-agent phase 2 trials conducted at Memorial Sloan-Kettering Cancer Center from 1990 to 2008 were reviewed. The study agents were suramin, all-transretinoic acid, topotecan, pyrazoloacridine, temozolomide, ixabepilone, and sunitinib. The major endpoints evaluated were response, progression-free survival (PFS), and overall survival (OS). Ninety patients (87 male, 3 female) were treated. The primary tumor site was testis in 65 patients, mediastinum in 17 patients, retroperitoneum in 4 patients, and other in 4 patients. Eighty-six patients had nonseminoma, and 4 patients had pure seminoma. Best responses were 1 (1%) partial response (ixabepilone), 15 (17%) stable disease, and 74 (82%) progressive disease. Median PFS and OS were 1.0 month (95% confidence interval [CI], 0.8-1.3) and 4.7 months (95% CI, 3.5-6.4), respectively. Eighty-six of the 90 patients have died. The 12- and 16-week PFS rates were 9% (95% CI, 3-15%) and 6% (95% CI, 1%-11%), respectively. Patients with refractory GCT progressed rapidly to these single agents. PFS and OS may be useful endpoints for designing phase 2 trials testing novel agents in this population. Twelve-week PFS (with comparison to the 9% benchmark rate reported herein) is the recommended endpoint for phase 2 trial design and median OS (using 4.7 months as the predicted median for the control arm) is suggested for phase 3 trials.

Treatment of patients with relapsed and/or cisplatin‐refractory metastatic germ cell tumours: an update

Since the introduction of cisplatin-based therapy in the late 1970s, germ cell tumours (GCT) have been one of the successes in oncology with high cure rates even in patients presenting with metastatic disease. For patients with relapse after cisplatin-based therapy, treatment is still curative in approximately 50% of the cases. Management options for these patients include surgery, radiotherapy and use of conventional dose or high-dose chemotherapy (HDCT). Therefore, treatment of relapsed or refractory patients is complex and there is no uniformly accepted approach available. Data comparing conventional dose and HDCT in the first salvage therapy is limited to one randomized trial which was not able to ultimately define optimal treatment. More recently, a large retrospective analysis of nearly 1600 patients not only identified prognostic factors in relapse, but retrospectively suggested a 10-15% benefit regarding overall survival for patients receiving HDCT plus autologous stem cell transplantation over patients receiving conventional-dose chemotherapy. Prognosis in multiply relapsed and primary cisplatin-refractory patients is generally poor. Currently, a number of mechanisms of cisplatin resistance and potential drug targets like global methylation and BRAF mutation status are under investigation in refractory GCT.

Phase II study of sunitinib malate in refractory germ cell tumors.

e15017 Background: Patients (pts) with platinum-refractory germ cell tumors (GCT) have very poor prognosis. Induction of angiogenesis is essential for tumor growth and metastasis. Vascular endothelial growth factor (VEGF) overexpression was most often seen in teratoma components of GCT. We hypothesized that inhibition of angiogenesis by multikinase oral inhibitor sunitinib could improve prognosis of these pts. The aim of the study was to investigate efficacy and toxicity of sunitinib in refractory GCT. Methods: Sunitinib was administered at a dose of 50mg daily for 4 weeks followed by 2 weeks off therapy. The response was evaluated every 12 weeks in a one-stage phase II trial. The primary end-point was 12-month post-treatment-initiation continuous progression-free survival (PFS) with type I and type II errors of <10%. For such study design 28 patients were planned for inclusion. Results: Ten patients were included in the trial from July 2008 till December 2010. Median age was 32 years (range: 19-55). With the exception of one patient, all were platinum-refractory. Patients were pretreated with median of 3 cisplatin-containing therapies (range: 3-6). The treatment was generally well tolerated. Toxicity grade 3 was the worst experienced toxicity (trombocytopenia in 2 pts, anemia in 1 pt and nausea and vomiting in 1 pt). Median follow-up has been 13 weeks (range: 5 - 47 weeks) and median follow-up of pts still alive has been 26 weeks (range: 5 - 47 weeks). A12-week PFS was 20%. Median PFS and overall survival was 10.8 and 13.1 weeks, respectively. One patient with teratocarcinoma achieved partial remission (PR) in lung, retroperitoneal lymph nodes, and decrease in AFP after two treatment-cycles but progressed after 4 cycles. Another patient with teratoma in primary tumor, but with high level of b-HCG at relapse, achieved PR in lung and lymph nodes after two treatment cycles, however with rapid elevation of b-HCG. Conclusions: Consistently with previous reports, we conclude that monotherapy with sunitinib has limited efficacy in heavily pretreated, unselected, refractory GCTs. Based on our observations we suggest that there might be some efficacy of sunitinib in GCTs with teratoma components that is in concordance with reported overexpression of VEGF in teratoma.

Superior survival after sequential high-dose chemotherapy (HDCT) as compared to single HDCT in patients with relapsed or refractory germ cell tumors (GCT): Six-year long-term follow-up of a prospective, randomized phase II trial.

4507 Background: Sequential and single high-dose chemotherapy (HDCT) can both be curative in patients (pts) with relapsed or refractory germ-cell tumors (GCT). The long-term efficacy of either moda...

Salvage chemotherapy with paclitaxel, gemcitabine, and nedaplatin (TGN) for cisplatin refractory heavily treated germ cell tumors.

e15089 Background: Only 20-30% of patients with cisplatin (CDDP) refractory germ cell tumor (GCT) will remain continuously disease free with salvage chemotherapy. The present study investigated the chemotherapy with paclitaxel (PTX) in combination with gemcitabine (GEM) and nedaplatin (CDGP), which is a derivative of CDDP, as salvage chemotherapy for CDDP refractory GCT. Methods: Between Jan 2003 and Dec 2010, 16 patients with CDDP refractory GCT were enrolled. All patients were male, with mean age 33 (range: 19-51). Median number of previous chemotherapy was 12 (range: 9-26) cycles. The combination chemotherapy consisted of PTX: 210 mg/m2 on day 1, CDGP 100 mg/m2 on day 2 and GEM: 1000mg/m2 on day 1 and 8 every three weeks. Results: A median of 4 cycles (range: 2-10) of TGN therapy was administered to 16 patients. Grade 3/4 toxicities were reported as follows: neutropenia: 100%, thrombocytopenia: 92%, anemia: 71%. No treatment related death was observed. Response rate was 56.3% (CR: 0 %, PRm-: 25%, PRm+: 31.3%, NC: 0%, PD: 43.7%). Unfortunately, no patients achieved a no evidence of disease status with a median duration of follow-up of 15 months (2-80 months). Six patients (37.5%) remain alive with disease. However, 10 patients (62.5%) died of the disease. Conclusions: This study demonstrates that combination chemotherapy with PTX, GEM and CDGP showed moderate anticancer activity for patients with CDDP refractory GCT without severe adverse events. These findings suggest that TGN therapy might be one of the options of salvage chemotherapy for CDDP refractory GCT and may be assessed as second or third line therapy.

A phase II multicenter evaluation of ARQ 197 monotherapy in patients with relapsed or refractory germ cell tumors (GCTs).

4638 Background: ARQ 197 is a selective, oral, non-ATP-competitive, small-molecule inhibitor of the c-MET receptor tyrosine kinase. Preclinical and phase I data suggested a possible role for c-MET in the pathophysiology of GCTs and a potential clinical benefit from ARQ 197 in GCT patients. Methods: Men (≥ 16 years of age) with relapsed or refractory, histologically confirmed, non-central nervous system GCTs received continuous oral ARQ 197 (360 mg twice daily in 28-day cycles) until progressive disease (PD) or unacceptable toxicity. Responses were assessed every 4 weeks during the first 4 cycles, and every 8 weeks thereafter per RECIST v1.1. The primary endpoint was objective response rate within the first 4 cycles, with study termination for < 2 responses amongst the first 21 patients (Simon 2-stage optimal design). Secondary endpoints included 12-week progression-free survival (PFS), overall survival (OS), and safety. Results: 27 patients (median age, 32 years) were enrolled from 9 sites in the US and Europe from February 2010 to November 2010. 25 had non-seminoma histology. Primary tumor sites included testis in 24, and mediastinum in 3. ECOG performance status was 0 (n = 9) or 1 (n = 18). All patients had received ≥ 2 prior lines of chemotherapy and 19/27 (70%) had received high-dose chemotherapy. Among 25 patients evaluable for efficacy, there were no objective responses and accrual was halted once the 21st patient became evaluable. Best response was stable disease in 7 and PD in 18. Median PFS was 32 days (95% CI = 29, 52) and 12-week PFS rate was 14%. Less than half (n = 12) patients have died. Reported grade 3/4 adverse events considered related to study drug were rare and included grade 3 pneumonia and grade 3 syncope (n = 1, each). Conclusions: ARQ 197 was well tolerated but did not demonstrate activity as a single agent in patients with relapsed/refractory GCTs. Correlative biologic data is pending but may provide insight into the lack of efficacy observed. Rapid accrual to this phase II trial was achieved in this rare patient population through multicenter collaboration. Future collaborative trials of novel targeted agents with sound biologic rationale are warranted in relapsed/refractory GCTs.