Platinum-refractory Germ Cell Tumors Research Articles

Response to guadecitabine (SGI-110) combined with cisplatin and gemcitabine (GCG) in platinum refractory germ cell tumors (GCTs).

e17057 Background: Treatment options for platinum refractory GCTs are limited. Platinum resistance derives, in part, from tumour suppressor gene promotor methylation. In vitro, this reverses on co-administration of a DNA hypomethylating agent. Guadecitabine is a next generation hypomethylating agent. SPIRE is a phase Ib/IIa clinical trial to establish a GCG dose/schedule. Methods: We report 2 platinum refractory GCT patients (pts) treated (txd) in SPIRE with GCG (guadecitabine 20 mg/m2, SC, day (D) 1-5; cisplatin 70 mg/m2, IV, D8; gemcitabine 1000 mg/m2, IV, D8 + 15; filgrastim 300 μg, SC, D15-21; q21). Results: Pt 1: 21 yo man, testicular mixed GCT (seminoma/malignant teratoma intermediate). Prior tx: 2001, orchidectomy; 2005, 3 x BEP (bleomycin, etoposide, cisplatin) + retroperitoneal lymph node dissection. 2015, 2 x TI (paclitaxel, ifosfamide), 3 x TIP (cisplatin, ifosfamide, paclitaxel); 2016, 3 x HDCE (high dose carboplatin/ etoposide + autologous stem cell transplantation); 2017, 6 x GOP (gemcitabine, oxaliplatin, paclitaxel). In 2017, received 6 x GCG in SPIRE for CT confirmed lung metastases (mets) and rising β-hCG (human chorionic gonadotropin). Response: RECIST stable disease with metabolic CR on PET in lungs and > 90% β-hCG reduction. In Cycle 6, pt developed symptomatic brain mets, treated with WBRT (40Gy, 20#) + cyberknife to the six mets completed 2018. Since 2018, ongoing complete marker and radiologic (brain and systemic) remission (20 months). Pt 2: 44 yo man, primary mediastinal non-seminomatous GCT. Prior tx: 2008, 4 x BEP + mediastinal mass resection; 2015, 4 x TIP; 2016, 1 x HDCE. In 2017, received 5 x GCG in SPIRE for a PET avid mediastinal/pulmonary relapse and AFP (alpha-fetoprotein) rise. Response: RECIST stable and > 50% AFP reduction for 6 months (subsequent progression with intracerebral metastasis). Treatment was well tolerated. Grade 4 neutropenia/ thrombocytopenia occurred in both and febrile neutropenia in pt 1. Both required a 25% dose reduction in Cis/Gem. Conclusions: GCG produced exceptional clinical responses in both platinum refractory GCT pts. Prospective evaluation is warranted. Clinical trial information: 16332228.

A phase I study of guadecitabine (SGI-110) plus cisplatin in patients with platinum refractory germ cell tumors.

408 Background: Guadecitabine (SGI-110) is a novel hypomethylating dinucleotide of decitabine and deoxyguanosine resistant to degradation by cytidine deaminase. Platinum-refractory germ cell tumors (GCT) showed significant DNA hypermethylation compared to platinum sensitive tumors. In preclinical studies, GCT were extremely sensitive to low dose decitabine which restored sensitivity to cisplatin in cell lines. We aimed to assess the safety and clinical activity of guadecitabine in combination with cisplatin in patients with platinum-refractory GCT. Methods: In this open-label, phase 1 study, patients with GCT refractory to or had relapsed after platinum-based treatment were treated with subcutaneous (SQ) guadecitabine, once-daily for 5 consecutive days, followed by cisplatin on day 8 with growth factor support (GFS) in a 28-day treatment cycle. A modified toxicity probability interval (mTPI) dose-escalation design was used in which we treated patients with guadecitabine doses of 30-45 mg/m2 plus cisplatin 100 mg/m2 up to 6 cycles until progression or intolerable toxicity. The primary objective was to assess safety and tolerability of the combination, determine the maximum tolerated dose (MTD). Secondary objective was objective response rate (ORR). Results: Fourteen patients with incurable disease were enrolled. Primary site were testis 11, mediastinum 2, and ovarian 1. All progressed after at least 2 lines of standard of care chemotherapy including HDCT. Dose-limiting toxicities were neutropenic fever. Most common toxicities were neutropenia (82% any grade), thrombocytopenia (42%), anemia (33%), neutropenic fever (8%), and diarrhea (8%). The maximum tolerated dose of guadecitabine was 30 mg/m2 x 5 days and cisplatin 100 mg/m2. We observed 2/14 complete response lasting more than 6 months, 2 partial response and 1 stable disease. ORR 28.5%. Conclusions: We report the first study of chemo-priming with epigenetic therapy in GCT. Guadecitabine 30 mg/m2 x 5 days and cisplatin 100 mg/m2 with GFS was safe and tolerable and showed promising activity with 4/14 responses in this highly treatment refractory patient population. Clinical trial information: NCT02429466.

A phase II study assessing the safety and efficacy of ASP1650 in male patients with incurable platinum refractory germ cell tumors.

TPS424 Background: Testicular cancer (TC) is the most common solid malignancy in men aged 15-35 yrs; germ cell tumors (GCTs) account for 95% of TC. Claudin 6 (CLDN6) is a tight junction membrane protein whose expression in normal tissue is confined to embryonic cells but is frequently aberrantly expressed in GCTs. ASP1650 (also known as IMAB027) is a monoclonal antibody targeted against CLDN6 that can induce antibody-dependent cell-mediated and complement-dependent cytotoxicity in CLDN6-expressing cells and has demonstrated potent antitumor effects in preclinical models of TC. Methods: This phase 2 study with a safety run-in (NCT03760081) will enroll ≤46 male patients (pts) with advanced GCTs who have had prior cisplatin-based combination chemotherapy and ≥1 salvage regimen. In the safety run-in, an initial ASP1650 dose level will be evaluated in 3 pts. If tolerated, a new cohort of 3 pts will begin at the next dose level per the Bayesian Optimal Interval Design. A Dose Evaluation Committee will assess tolerability and determine maximum tolerated dose. Once the recommended phase 2 dose (RP2D) has been established, ≤34 pts will be enrolled in phase 2 and will receive ASP1650 in 2-week cycles for up to 12 cycles or until study discontinuation criteria is met. Phase 2 of the study will utilize a Simon’s 2-stage design to allow for early termination. In stage I, 13 pts, including pts from the RP2D cohort of the safety run-in, will be evaluated for response. If there is ≤1 response among these 13 pts, the study will be stopped, otherwise an additional 21 pts will be enrolled in stage II. Primary endpoints of the study include establishment of the RP2D and confirmation of overall response rate, as assessed by modified RECIST v1.1 response criteria (RECIST v1.1 + serum tumor markers [βhCG and AFP]). Secondary endpoints include the determination of safety/tolerability and pharmacokinetic profiles as well as other efficacy measures (eg, clinical benefit rate; progression-free survival; change in serum tumor biomarkers). Enrollment is currently ongoing; as of Sept 12, 2019, 6 pts have enrolled and 2 are still on active treatment. Clinical trial information: NCT03760081.

Abstract 1386: Safety and tolerability of guadecitabine (SGI-110) plus cisplatin in patients with platinum refractory germ cell tumors (GCT): A phase 1 study

Abstract BACKGROUND: Guadecitabine (SGI-110) is a novel hypomethylating dinucleotide of decitabine and deoxyguanosine resistant to degradation by cytidine deaminase. Germ cell tumor including platinum-resistant embryonal carcinoma cells lines are extremely sensitive to hypomethylating agents and low dose decitabine can restore cisplatin sensitivity in cell lines. We aimed to assess the safety and clinical activity of guadecitabine in combination with cisplatin in patients with platinum-refractory GCT. METHODS: In this open-label, phase 1 study, patients with GCT refractory to or had relapsed after platinum-based treatment were treated with subcutaneous (SQ) guadecitabine, once-daily for 5 consecutive days, followed by cisplatin on day 8 in a 28-day treatment cycle. A modified toxicity probability interval (mTPI) dose-escalation design was used in which we treated patients with guadecitabine doses of 30-45 mg/m2 plus cisplatin 100 mg/m2 up to 6 cycles until progression or intolerable toxicity. The primary objective was to assess safety and tolerability of guadecitabine in combination with cisplatin, determine the maximum tolerated and identify the recommended phase 2 dose of guadecitabine. Safety analyses included all patients who received at least one dose of guadecitabine. Pharmacodynamic analyses to determine the biologically effective dose included all patients for whom samples were available. This study is registered with ClinicalTrials.gov, number NCT02429466. FINDINGS: Between 2015 and 2017, we enrolled and treated 10 patients. Grade 3 or 4 adverse events were febrile neutropenia, thrombocytopenia, anemia, and diarrhea. The most common serious adverse events were febrile neutropenia and thrombocytopenia. Guadecitabine 45 mg/m2 was associated with prolonged SAE and felt to be unsafe to continue. The maximum tolerated dose was 30 mg/m2 daily × 5. Two patients achieved a complete response to treatment lasting more than 6 months. INTERPRETATION: Guadecitabine SQ at 30 mg/m2 daily × 5 is well tolerated and is clinically and biologically active in patients with platinum-refractory GCT. The study is still ongoing. Citation Format: Costantine Albany, Neda S. Hashemi, Fang Fang, James Lowder, Lawrence Einhorn, Kenneth Nephew. Safety and tolerability of guadecitabine (SGI-110) plus cisplatin in patients with platinum refractory germ cell tumors (GCT): A phase 1 study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1386.

Safety and tolerability of guadecitabine (SGI-110) plus cisplatin in patients (pts) with platinum-refractory germ cell tumors (GCT): Preliminary results from an open label phase 1b study.

e16545Background: Preclinical data suggests platinum resistant embryonal carcinoma (EC) cell lines are sensitive to hypomethylating agents. Guadecitabine (G), a novel hypomethylating dinucleotide o...

Low CD34+ Cell Doses Are Associated with Increased Cost and Worse Outcome after Tandem Autologous Stem Cell Transplantation in Patients with Relapsed or Refractory Germ Cell Tumors

Tandem autologous stem cell transplantation (ASCT) improves long-term survival of platinum-refractory germ cell tumors (GCT) patients. Studies, predominantly in lymphoma, showed that CD34+ cell doses > 5.0 × 106/kg/single transplant led to decreased resource utilization. Because most GCT patients have received prior cisplatin-based treatment, collecting >10 × 106 CD34+ cells/kg is challenging. We analyzed the effect of CD34+ cell dose on resource utilization and outcome in 131 GCT patients, median age 29.5 years (range, 16 to 58), undergoing tandem ASCT. Of 262 individual transplants performed, 120 were performed as inpatient and 142 as planned outpatient. Overall, median CD34+ dose per transplant was 3.1 × 106/kg (range, 0.8 to 16.0), with no significant difference between inpatient and outpatient transplants. Patients were divided into quartiles based on the CD34 cell dose infused: Q1, 0.8 to 1.9 × 106/kg; Q2, 2.0 to 2.9 × 106/kg; Q3, 3.0 to 4.1 × 106/kg; and Q4, 4.2 to 16.0 × 106/kg. For all patients higher CD34+ cell doses were associated with significantly shorter times to neutrophil (P < .001) and platelet recovery (P < .001). For inpatient transplants higher CD34+ doses were significantly associated with shorter length of hospital stay (P < .001), fewer days of filgrastim (P < .001), i.v. antibiotic (P = .012) and antifungal (P = .03) usage; and fewer RBC (P = .001) and platelet units transfused (P < .001), resulting in overall lower cost of care (P < .001). Of the 142 planned outpatient transplants, 100 admissions were required for a median length of hospital stay of 7.0 days (range, 1 to 18). Although there was no significant difference in the rates of hospitalization between patients in different CD34+ cell dose quartiles, a significant trend was observed for shorter hospitalization (P = .01) and fewer RBC (P = .002) and platelet (P = .005) transfusions with higher CD34+ cell dose quartile. Patients receiving CD34+ cell doses in the lowest dose quartile (Q1) had significantly worse progression-free survival and overall survival compared with patients receiving higher CD34+ cell doses. Overall, resource utilization, including cost of care, is significantly reduced when patients receive higher CD34+ cell doses, indicating greater efforts to improve peripheral blood stem cell collection in this population are needed.

Phase II trial of pembrolizumab in patients with platinum refractory germ-cell tumors: a Hoosier Cancer Research Network Study GU14-206

Despite remarkable results with salvage standard-dose or high-dose chemotherapy ∼15% of patients with relapsed germ-cell tumors (GCT) are incurable. Immune checkpoint inhibitors have produced significant remission in multiple tumor types. We report the first study of immunotherapy in patients with GCT. Single arm phase II trial investigating pembrolizumab 200 mg i.v. Q3weeks until disease progression in patients with relapsed GCT and no curable options. Patients age ≥18 with GCT who progressed after first-line cisplatin-based chemotherapy and after at least one salvage regimen (high-dose or standard-dose chemotherapy) were eligible. Centrally assessed programmed death-ligand 1 (PD-L1) on tumor and infiltrating immune cells was scored. Primary end point was overall response rate using immune-related response criteria. Simon two-stage design with type I error 20% and power 80% was utilized. Twelve male patients were enrolled. Median age was 38 years. All patients had nonseminoma. Primary site was testis (11) or mediastinum (1). Median AFP 615 (range 1-32, 760) and hCG 4 (range 0.6-37, 096). Six patients had late relapse (>2 years). Median number of previous chemotherapy regimens was 3. Six patients received prior high-dose chemotherapy. Two patients had positive PD-L1 staining (H-score 90 and 170). Median number of pembrolizumab doses was 2 (range 1-8). There were six grade 3 adverse events. No immune-related adverse events were reported. No partial or complete responses were observed. Two patients achieved radiographic stable disease for 28 and 19 weeks, respectively; both had continued rising AFP level despite radiographic stability and had negative PD-L1 staining. This is the first reported trial evaluating immune checkpoint inhibitors in GCT. Pembrolizumab is well tolerated but does not appear to have clinically meaningful single-agent activity in refractory GCT. NCT02499952.

Phase II trial of pembrolizumab in patients (pts) with incurable platinum refractory germ cell tumors (GCT).

4520 Background: Despite remarkable results with salvage standard-dose (SDCT) or high-dose chemotherapy (HDCT), about 15% of pts with relapsed GCT are incurable. Immune therapy with Pembrolizumab is a novel approach for salvage in pts with metastatic GCT. Methods: Single arm phase 2 trial investigating pembrolizumab 200mg IV Q3weeks until disease progression in pts with relapsed GCT and no curable options. Pts age≥18 with metastatic GCT who progressed after first line cisplatin-based chemotherapy and after at least 1 salvage regimen (HDCT or SDCT) were eligible. Centrally assessed PD-L1 on tumor infiltrating immune cells using PD-L1 (22C3) assay was scored as 0, 1, 2, 3 along with PD-L1 expression score (H-score) incorporating intensity of staining. Pts were eligible irrespective of PD-L1 expression status. The primary endpoint was overall response rate using immune-related response criteria. Simon’s 2-stage design required response in ≥ 1/12 pts to proceed to stage 2 enrolling 8 more pts for a total of 20. Results: 12 male pts were enrolled. Median age 38 (range, 27-55). All pts had non-seminoma. Primary tumor site was testis in 11 pts and mediastinum in 1. Median AFP 615 (range, 1-32,760) and hCG 4 (range, 0.6-37,096). 5 pts had late relapse ( &gt; 2years). Median number of previous chemotherapy regimens was 3 (range, 1-6). 6 pts received prior HDCT. 2 pts had positive PD-L1 staining (H-score 90 and 170). Median number of deliverable pembrolizumab doses was 2 (range, 1-8). There were 5 grade 3 adverse events, with 3 events possibly related to study treatment (chest pain, hyperglycemia, abdominal pain). No partial or complete responses were observed. 2 pts achieved stable disease for 12 and 9 weeks respectively; 10 pts had progression of disease as their best response. The 2 pts with stable disease had continued rising AFP level despite radiographic stability; both had negative PD-L1 staining. Conclusions: This is the first reported trial evaluating immune checkpoint inhibitors in GCT. Although 2 pts had stable disease, each had rising tumor markers suggesting continued treatment resistance. Pembrolizumab is well tolerated but does not appear to have clinically meaningful single-agent activity in refractory GCT. Clinical trial information: NCT02499952.

Low hypoxia inducible factor-1α (HIF-1α) expression in testicular germ cell tumors - a major reason for enhanced chemosensitivity?

The molecular basis for enhanced chemosensitivity of testicular germ cell tumors (GCT) has been an area of great interest, as it could potentially give us therapeutic leads in other resistant malignancies. Thus far, however, the increased sensitivity of GCT has been variously attributed to multiple factors — an inability to detoxify cisplatin, a lack of export pumps, an inability to repair the DNA damage, an intact apoptotic cascade and lack of p53 mutation; but a unifying underlying etiology leading to the aforementioned processes and having a translational implication has so far been elusive. Herein, we offer evidence to support a potential significant role for the previously demonstrated low hypoxia inducible factor-1α (HIF-1α) expression in mediating the general exquisite chemosensitivity of testicular GCT, through the aforementioned processes. This molecular mechanism based hypothesis could have a significant translational implication in platinum refractory GCT as well as other platinum resistant malignancies.

Epigenetic Targeting of Platinum Resistant Testicular Cancer

The involvement of epigenetic aberrations in the development and progression of tumors is now well established. However, little is known of the epigenetic alterations in testicular cancer and particularly in platinum refractory germ cell tumors. Germ cell derived testicular cancers, as compared to somatic tumors, appear to have a unique epigenetic profile that features more extensive DNA hypomethylation. Emerging data from clinical specimens suggest that epigenetic aberrations, especially DNA hypermethylation, can contribute to chemotherapy resistance and poor clinical outcomes in testicular germ cell tumors. Recent data indicate that testicular cancer cells, even those resistant to platinum, are highly sensitive to low doses of demethylating agents. Based on these promising preclinical studies, we suggest that DNA methylation inhibitors in combination with chemotherapeutic agents may offer a path to overcome acquired drug resistance in testicular cancer, laying the foundation and rationale for testing this class of epigenetic drugs in the clinical setting. In this mini-review we provide a brief overview of the promise of DNA methylation therapy to treat patients with refractory cancer of the testes.

Platinum-refractory germ cell tumors: an update on current treatment options and developments.

In general, 50% up to 80% of metastasized germ cell tumor patients can be cured by platinum-based chemotherapy. However, 3-5% of patients will still die of platinum-refractory disease and new systemic treatment options are needed to improve treatment success in this difficult setting. This review aims to give an overview on treatment options and current developments in the field of platinum-refractory male germ cell tumors. A comprehensive literature search was conducted searching PubMed, Medline, Cochrane and Embase to identify clinical trials regarding the treatment of platinum-refractory disease. ASCO, EAU and ESMO conference proceedings were searched to identify unpublished results of relevant trials. Comprehensive review papers were hand searched for additional references. Clinicaltrials.gov was checked for ongoing clinical trials in the field of platinum-refractory germ cell tumors. Outcome of platinum-refractory disease remains poor. Single-agents with reasonable activity are gemcitabine, oxaliplatin and paclitaxel, but complete remissions resulting in long-term survival could not be achieved. The triple-combination of gemcitabine, oxaliplatin and paclitaxel followed by resection of residual masses provides the best outcomes with objective responses in 51% of patients and long-term survival in approximately 10-15%. To date, no molecularly targeted agent has shown reasonable activity. Treatment options for platinum-refractory disease are limited, but a small subset of patients may achieve long-term disease-free survival by multimodal treatment. The potential of novel targeted agents, i.e. by immune-checkpoint-inhibition remains to be defined.

A phase II single arm multi-center trial evaluating the efficacy of pembrolizumab in the treatment of patients (pts) with incurable platinum refractory germ cell tumors (GCT).

TPS4579Background: Initial cisplatin-based combination chemotherapy will cure 80% of pts with metastatic GCT. Pts who relapse after initial chemotherapy can still be cured with second and even thir...

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.

Phase I Study of Flavopiridol with Oxaliplatin and Fluorouracil/Leucovorin in Advanced Solid Tumors

Flavopiridol, a cyclin-dependent kinase inhibitor, has promising clinical activity when combined with chemotherapy. Preclinical data indicate that flavopiridol enhances oxaliplatin- and fluorouracil (5FU)-induced apoptosis in a sequence-dependent manner. We conducted a phase I trial of flavopiridol + FOLFOX (folinic acid, 5FU, and oxaliplatin) for advanced solid tumors. Flavopiridol was administered every 2 weeks with oxaliplatin before 5FU, based on sequence-dependent growth inhibition. Flavopiridol pharmacokinetics and p53 status were evaluated. Forty-eight patients were treated on study. With dose escalation of oxaliplatin (85 mg/m(2)) and 5FU (2,400 mg/m(2)), dose-limiting toxicities included hyponatremia, thrombocytopenia, and neutropenia. 5FU was subsequently reduced to allow for dose escalation of flavopiridol. Dose-limiting toxicities with escalation of flavopiridol were nausea, vomiting, and neutropenia. The maximum tolerated dose was 70 mg/m(2) flavopiridol, 85 mg/m(2) oxaliplatin, and 1,800 mg/m(2) 5FU continuous infusion over 48 hours. Clinical activity was noted in platinum-refractory germ cell tumors: 3 of 9 (33%) evaluable patients showed a partial response on imaging and 7 of 10 (70%) had a decline in serum tumor markers. Responses were also observed in pancreatic, gastric, and sweat gland tumors. Flavopiridol pharmacokinetics had significant interpatient variability. At the maximum tolerated dose, tumor samples were p53 mutant (>30% positive cells) for responders and p53 wild-type for nonresponders. Flavopiridol with FOLFOX is a safe and tolerable regimen. Promising clinical activity was seen across tumor types. Encouraging results in the platinum-refractory germ cell tumor population has prompted a phase II trial that is currently open for accrual.