Multicenter phase-II Trial Research Articles

Intensity-modulated radiotherapy alone compared with intensity-modulated radiotherapy plus concurrent chemotherapy in intermediate-risk nasopharyngeal carcinoma : Aprospective multicenter phaseII trial.

This study aimed to investigate the clinical benefit of adding concurrent chemotherapy to intensity-modulated radiotherapy (IMRT) for nasopharyngeal carcinoma (NPC) patients with an intermediate risk (stageII and T3N0M0). Amulticenter phaseII randomized trial was conducted in intermediate-risk NPC patients. Enrolled patients were previously untreated and aged ranged from 18 to 70years without severe coexisting diseases. Patients were randomly assigned to receive IMRT alone or IMRT+concurrent chemotherapy (CC; three cycles of 80 mg/m2 cisplatin every 3weeks). Primary endpoint was defined as 3‑year progression-free survival (PFS). The secondary endpoints were distant metastasis-free survival (DMFS), locoregional relapse-free survival (LRRFS), overall survival (OS), and treatment-associated toxicity. We registered this study with Chinese Clinical Trial Registry (CliCTR1800017132; registered July13, 2018, study start July13, 2018). From November 2015 to July 2019, 42patients with stageII and T3N0M0 NPC were enrolled; 20patients received IMRT alone while 22patients received IMRT+CC. After amedian of 58months of follow-up, we estimated the 3‑year PFS rates as 90% (IMRT group) and 86.4% (IMRT+CC group; hazard ratio 1.387, 95% confidence interval 0.240-8.014; P = 0.719). The 3‑year PFS, OS, and cumulative DMFS and LRRFS showed no significant differences between the two groups (P > 0.05). However, the IMRT group displayed alower incidence of nausea/vomiting, leucopenia, and dry mouth than the IMRT+CC group. Adding CC to IMRT provided no survival benefit but increased treatment-associated toxicities in patients with intermediate-risk NPC.

Reduced Intensity Haploidentical Bone Marrow Transplantation in Adults with Severe Sickle Cell Disease: BMT CTN 1507

Background: Allogeneic hematopoietic stem-cell transplantation has curative potential for sickle cell disease (SCD). Event-free survival (EFS) in children with SCD is >90% after a bone marrow transplant (BMT) from a myeloablative matched sibling donor (MSD). Unfortunately, <15% of patients with SCD have MSD, and myeloablative conditioning can be prohibitively toxic in adults with SCD. Reduced intensity HLA-haploidentical BMT with post-transplant cyclophosphamide (PTCy) has been shown in small studies to expand the donor pool with encouraging results. Still, concerns about graft failure and graft-versus-host disease (GVHD) persist. We present the results of a Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 1507, multi-center single-arm, phase-II, prospective clinical trial (clinicaltrials.gov #NCT03263559) of haploidentical-BMT with PTCy to estimate EFS at 2-years in adults with severe SCD. Pediatric stratum data is not included in the data presentation and will be available in 2-years. Study Design and Methods: Eligibility: SCD patients aged 15.00-45.99 years with prior stroke, recurrent ACS or pain, chronic transfusion regimen, or tricuspid valve regurgitant jet velocity (TRJV) ≥2.7 m/sec were eligible. Participants were required to have an HLA-haploidentical first-degree relative donor, willing and able to donate bone marrow. The primary objective was EFS (survival without primary or secondary graft failure or second infusion of stem cells) at 2 years after haploidentical-BMT. Secondary objectives included determining the impact on clinical and laboratory manifestations of SCD and other transplant outcomes at 2 years post haploidentical-BMT. The protocol was opened for enrollment on 10/5/2017, completed accrual on 01/6/2021, and data are current as of 8/2023. Preconditioning with hydroxyurea (HU) 30mg/kg/day (Day-70 to Day-10); Conditioning regimen included Thymoglobulin (rATG), Thiotepa, Fludarabine, Cyclophosphamide, and Total Body Irradiation (TBI). GVHD prophylaxis included PTCy, sirolimus, and mycophenolate mofetil, figure. Results: A total of 54 eligible participants enrolled from 19 sites; 42 (78%) proceeded to transplant. Amongst enrolled participants, 59.3% are male, 92.6% are Black, and 3.7% are Hispanic. 10 participants started HU but did not proceed to BMT, and 2 did not start HU or proceed to BMT. Reasons included donor issues (n=4), withdrawal of consent (n=2), insurance coverage (n=2), death (n=1), and other (n=3). 38/42 (90%) participants completed the study as planned; 2 participants withdrew consent, and 2 were lost to follow-up. The median age was 22.8 years at enrollment; 47/54 (87%) of enrolled participants had Hemoglobin SS disease, 40/54 (74.1%) had a Lansky/Karnofsky score of 90-100 at baseline, and 41/54 (75.9%) had an HLA match score of 4/8. Recurrent vaso-occlusive pain episodes (38.9%), acute chest syndrome (16.8%), and overt stroke (16.7%) were the most common indications for transplant. Only 13 (31%) participants achieved the intended 30 mg/kg/day dosing of HU preconditioning. Estimated 2-year EFS is 88% (95% CI: 73.5%, 94.8%); all except one qualifying event occurred within 12 months. The 2-year overall survival (OS) post-HU was 93.0% (95% CI: 79.8%, 97.7%), and the 2-year OS post-transplant was 95.0% (95% CI: 81.5%, 98.7%); 2 (4.8%) participants had primary graft failure, and 1 (2.4%) had secondary graft failure before day +100. The cumulative incidence of grades II-IV acute GVHD at day 100 was 26.2% (95% CI: 14.0%, 40.2%), and grades III-IV acute GVHD at day 100 was 4.8% (95% CI: 0.9%, 14.4%). There were two deaths in the first year post-BMT (1 -organ failure; 1-ARDS), none in the second year; 33 (78.6%) participants reported at least one re-admission post-BMT, mainly due to either bacterial infection (n=41) or viral reactivation (n=36), table. Conclusion: This multi-center phase-II trial of a reduced intensity haploidentical-BMT in adults with SCD shows durable donor engraftment at 2-years with low mortality. The 2-year EFS and OS are comparable to that reported after MSD myeloablative BMT. These results support haploidentical BMT with PTCy as a suitable and tolerable curative therapy for adults with SCD and severe end-organ toxicity such as stroke and pulmonary hypertension, a population typically excluded from participating in myeloablative gene therapy and gene editing trials.

Toripalimab plus chemotherapy as second-line treatment in previously EGFR-TKI treated patients with EGFR-mutant-advanced NSCLC: a multicenter phase-II trial

This multicenter phase-II trial aimed to investigate the efficacy, safety, and predictive biomarkers of toripalimab plus chemotherapy as second-line treatment in patients with EGFR-mutant-advanced NSCLC. Patients who failed from first-line EGFR-TKIs and did not harbor T790M mutation were enrolled. Toripalimab plus carboplatin and pemetrexed were administrated every three weeks for up to six cycles, followed by the maintenance of toripalimab and pemetrexed. The primary endpoint was objective-response rate (ORR). Integrated biomarker analysis of PD-L1 expression, tumor mutational burden (TMB), CD8 + tumor-infiltrating lymphocyte (TIL) density, whole-exome, and transcriptome sequencing on tumor biopsies were also conducted. Forty patients were enrolled with an overall ORR of 50.0% and disease-control rate (DCR) of 87.5%. The median progression free survival (PFS) and overall survival were 7.0 and 23.5 months, respectively. The most common treatment-related adverse effects were leukopenia, neutropenia, anemia, ALT/AST elevation, and nausea. Biomarker analysis showed that none of PD-L1 expression, TMB level, and CD8 + TIL density could serve as a predictive biomarker. Integrated analysis of whole-exome and transcriptome sequencing data revealed that patients with DSPP mutation had a decreased M2 macrophage infiltration and associated with longer PFS than those of wild type. Toripalimab plus chemotherapy showed a promising anti-tumor activity with acceptable safety profiles as the second-line setting in patients with EGFR-mutant NSCLC. DSPP mutation might serve as a potential biomarker for this combination. A phase-III trial to compare toripalimab versus placebo in combination with chemotherapy in this setting is ongoing (NCT03924050).

The Janus kinase 1/2 inhibitor ruxolitinib in COVID-19 with severe systemic hyperinflammation

A subgroup of patients with severe COVID-19 suffers from progression to acute respiratory distress syndrome and multiorgan failure. These patients present with progressive hyperinflammation governed by proinflammatory cytokines. An interdisciplinary COVID-19 work flow was established to detect patients with imminent or full blown hyperinflammation. Using a newly developed COVID-19 Inflammation Score (CIS), patients were prospectively stratified for targeted inhibition of cytokine signalling by the Janus Kinase 1/2 inhibitor ruxolitinib (Rux). Patients were treated with efficacy/toxicity guided step up dosing up to 14 days. Retrospective analysis of CIS reduction and clinical outcome was performed. Out of 105 patients treated between March 30th and April 15th, 2020, 14 patients with a CIS ≥ 10 out of 16 points received Rux over a median of 9 days with a median cumulative dose of 135 mg. A total of 12/14 patients achieved significant reduction of CIS by ≥25% on day 7 with sustained clinical improvement in 11/14 patients without short term red flag warnings of Rux-induced toxicity. Rux treatment for COVID-19 in patients with hyperinflammation is shown to be safe with signals of efficacy in this pilot case series for CRS-intervention to prevent or overcome multiorgan failure. A multicenter phase-II clinical trial has been initiated (NCT04338958).

New lessons learned in T-PLL: results from a prospective phase-II trial with fludarabine–mitoxantrone–cyclophosphamide–alemtuzumab induction followed by alemtuzumab maintenance

Clinical trials in T-cell prolymphocytic leukemia (T-PLL) are scarce. Based on a precursor study testing fludarabine, mitoxantrone, and cyclophosphamide followed by alemtuzumab (FMC-A), we aimed to improve this regimen by upfront combining subcutaneous (s.c.) alemtuzumab with FMC for four cycles followed by an alemtuzumab-maintenance (FMCA + A). This prospective multicenter phase-II trial assessed response, survival, and toxicity of that regimen administered to pretreated (n = 4) and treatment-naïve (n = 12) T-PLL patients. The best overall response rate after FMCA was 68.8% (n = 11) including five CRs (31.3%) and six PRs (37.5%). Six patients entered the alemtuzumab-maintenance. Median overall and progression-free survival was 16.7 and 11.2 months, respectively. Hematologic toxicities were the most frequent grade 3/4 side effects. A reduced incidence of CMV-reactivations was attributed to the prophylactic administration of valganciclovir. Overall, FMCA + A did not improve the efficacy of the FMC-A-regimen or of single i.v. alemtuzumab. It suggests that a chemotherapy backbone prevents efficient alemtuzumab dosing and confirms that intravenous alemtuzumab is to be preferred over its s.c. route in T-PLL.Trial registration: ClinicalTrials.gov identifier: NCT01186640.

With a Little Help from My Friends: The Role of Intraoperative Fluorescent Dyes in the Surgical Management of High-Grade Gliomas.

High-grade gliomas (HGGs) are the most frequent primary malignant brain tumors in adults, which lead to death within two years of diagnosis. Maximal safe resection of malignant gliomas as the first step of multimodal therapy is an accepted goal in malignant glioma surgery. Gross total resection has an important role in improving overall survival (OS) and progression-free survival (PFS), but identification of tumor borders is particularly difficult in HGGS. For this reason, imaging adjuncts, such as 5-aminolevulinic acid (5-ALA) or fluorescein sodium (FS) have been proposed as superior strategies for better defining the limits of surgical resection for HGG. 5-aminolevulinic acid (5-ALA) is implicated as precursor in the synthetic pathway of heme group. Protoporphyrin IX (PpIX) is an intermediate compound of heme metabolism, which produces fluorescence when excited by appropriate light wavelength. Malignant glioma cells have the capacity to selectively synthesize or accumulate 5-ALA-derived porphyrins after exogenous administration of 5-ALA. Fluorescein sodium (FS), on the other hand, is a fluorescent substance that is not specific to tumor cells but actually it is a marker for compromised blood-brain barrier (BBB) areas. Its effectiveness is confirmed by multicenter phase-II trial (FLUOGLIO) but lack of randomized phase III trial data. We conducted an analytic review of the literature with the objective of identifying the usefulness of 5-ALA and FS in HGG surgery in adult patients.

Low Incidence of Tumor Lysis Syndromes (TLS) and Infusion Related Reactions (IRR) in the CLL2-Bag Trial Evaluating a Sequential Treatment of Bendamustine (B), Obinutuzumab (GA101, G) and Venetoclax (ABT-199, A) in Patients with Chronic Lymphocytic Leukemia (CLL): Interim Safety Results of a Phase-II-Trial of the German CLL Study Group (GCLLSG)

Low Incidence of Tumor Lysis Syndromes (TLS) and Infusion Related Reactions (IRR) in the CLL2-Bag Trial Evaluating a Sequential Treatment of Bendamustine (B), Obinutuzumab (GA101, G) and Venetoclax (ABT-199, A) in Patients with Chronic Lymphocytic Leukemia (CLL): Interim Safety Results of a Phase-II-Trial of the German CLL Study Group (GCLLSG)

CLL2-BIG - a Novel Treatment Regimen of Bendamustine Followed By GA101 and Ibrutinib Followed By Ibrutinib and GA101 Maintenance in Patients with Chronic Lymphocytic Leukemia (CLL): Results of a Phase II-Trial

CLL2-BIG - a Novel Treatment Regimen of Bendamustine Followed By GA101 and Ibrutinib Followed By Ibrutinib and GA101 Maintenance in Patients with Chronic Lymphocytic Leukemia (CLL): Results of a Phase II-Trial

Abstract IA23: Leukemia development and the microenvironment

Abstract Myeloproliferative neoplasms (MPNs) are hematological malignancies originated by hematopoietic stem cells (HSCs) carrying mutations, most frequently in JAK2, CALR or MPL genes. These diseases, which cannot be cured in most cases, are characterized by overproduction of myeloid and erythroid-megakaryocytic lineages. However, it remains unclear how some mutations, that are frequently common in disparate MPNs, can cause different clinical outcomes. Moreover, current treatments are mostly symptomatic and are only capable of slowing down the disease, but generally they cannot eradicate it. This suggests that other factors critically contribute to MPN progression. Our research group has demonstrated specific alterations of the microenvironment of HSCs in MPN. We have shown that mutated HSCs can only expand and trigger disease after damaging bone marrow (BM) nerve terminals and mesenchymal stem cells (BMSCs), overcoming the control that this environment can exert over mutated HSC proliferation and migration. Therefore, preserving the HSC niche might be a complementary strategy to treat these diseases. This approach is being currently tested in a multicenter phase-II clinical trial (clinicaltrials.gov identifier NCT02311569). MPNs can be considered a pre-leukemic state since MPN patients have a higher risk of developing acute myeloid leukemia (AML), which is highly aggressive and exhibits poor response to chemotherapy. Work from other groups and our preliminary data suggest that acute leukemic cells can transform the BM microenvironment to promote leukemogenesis. We have studied the contribution of nestin+ BMSCs to the development of acute myeloid leukemia (AML) induced by the MLL-AF9 oncogene. For this purpose we have used a doxycycline-inducible rtTA;MLL-AF9 mouse strain, which closely mimics the human disease. Development of AML in rtTA;MLL-AF9 mice caused a significant reduction of stromal cells in the BM but, contrasting our previous findings in MPN, it did not seem to affect the number of BM nestin+ cells. To study the possible contribution of nestin+ cells to leukemia development, we partially depleted nestin+ cells by inducing diphtheria toxin expression in these cells using Nestin-creERT2;iDTR mice previously transplanted in a competitive fashion with preleukemic and normal BM cells. We have shown previously that nestin+ cell depletion using this strategy can accelerate MPN. In contrast, nestin+ cell depletion had the opposite effect in AML, since it selectively diminished leukemia burden in BM, spleen and blood, and reduced the number of primitive leukemic cells, without affecting normal residual hematopoiesis. Combined nestin+ cell depletion and standard chemotherapy further exaggerated the elimination of BM leukemic cells. Among primitive leukemic cells, MLL-AF9+ lin- ckitlow sca1- cells were most significantly expanded in leukemia and were most significantly decreased upon nestin+ cell ablation, an effect that seemed to be further enhanced by simultaneous chemotherapy. This was not associated with detectable changes in the cell cycle profile of leukemic progenitors. Moreover, non-proliferative (ki67-) lin- cells were not found enriched in the vicinity of nestin+ cells, and Cxcl12 deletion in nestin+ cells, which increased thrombocytosis in our previous MPN studies, did not affect AML progression. In order to identify changes in leukemic progenitors following Nes+ cell depletion, we compared the gene expression profiles of lin- ckitlow sca1- cells isolated from control and Nes+ cell-depleted, MLL-AF9 expressing mice. Next-generation sequencing assays identified downregulation of gene sets related to HSC self-renewal, protein synthesis and degradation, and mitochondrial respiration in leukemic progenitors obtained from Nes+ cell-depleted bone marrow. The data suggests that AML-AF9+ leukemic progenitors impose changes in Nes+ cells that promote leukemogenesis. Using a novel co-culture system, we are currently testing possible mediators of the pro-survival effect of BMSCs over leukemic progenitors. Citation Format: Abel Sánchez-Aguilera, Vaia Stavropoulou, Daniel Martín-Pérez, Alexandar Tzankov, Jürg Schwaller, Simón Méndez-Ferrer. Leukemia development and the microenvironment. [abstract]. In: Proceedings of the Fourth AACR International Conference on Frontiers in Basic Cancer Research; 2015 Oct 23-26; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2016;76(3 Suppl):Abstract nr IA23.

663P - Multicenter Phase Ii Trial of Adjuvant S-1 Plus Docetaxel for 6 Months in Patients with Pathological Stage III Gastric Cancer (Ogsg-1002)

ABSTRACT Aim: We have previously indicated the torelability and safety of adjuvant S-1 plus Docetaxel for 3 months after D2 gastrectomy in patients with pathological stage III gastric cancer (OGSG-0604). To achieve the further treatment outcome, we conducted a phase II study to evaluate the feasibility of S-1 plus Docetaxel for 6 months after D2 gastrectomy in counterpart patients. Methods: Eligibility criteria included ECOG-PS of 0 or 1, age between 20 and 80 years and histologically proven stage III gastric cancer after R0 gastrectomy with D2 lymphadenectomy. Enrolled patients received 40mg/m2 Docetaxel on day1 intravenously and 80mg/m2 oral S-1 on day1-14 every 3 weeks (one cycle). This 3–week cycle was repeated for 8 cycles (for 6 months), followed by S-1 monotherapy until 1 year after surgery. The primary endpoint was feasibility of S-1 plus Docetaxel for 8 cycles. Results: A total of 62 patients (32 stage IIIA, 30 IIIB, according to the 13th Japanese Classification of Gastric Carcinoma) were enrolled in this study from 14 institutes between Dec 2010 and Dec 2012. Forty-eight patients (77.4%, 95%CI 65.0-87.1%) completed the planned 8 cycles of S-1 plus Docetaxel and the proportion of patients completed planned cycles was comparable with that of 4 cycles (OGSG-0604). Forty-two patients completed the consequent S-1 monotherapy until 1 year after surgery and 2 patients were ongoing of consequent S-1 monotherapy. This doublet regimen was well tolerated, with 19% of Grade 4 neutropenia, 18% of Grade 3 anorexia and 10 % of Grade3 fatigue, while no febrile neutropenia, grade 4 non-hematological toxicities and treatment related death were observed. Conclusions: Adjuvant S-1 plus Docetaxel for 6 months in patients with stage III gastric cancer was well tolerated after D2 gastrectomy and will be a candidate for future phase III trials studying the optimal adjuvant chemotherapy regimen for stage III gastric cancer. Disclosure: All authors have declared no conflicts of interest.

589P - Multicenter Phase Ii Trial of Neoadjuvant Chemotherapy with Mfolfox6 for Stage Ii/Iii Rectal Cancer with a T3/T4 Tumor Fact Trial

ABSTRACT Aim: The efficacy and safety of neoadjuvant chemotherapy with modified FOLFOX6 (mFOLFOX6) for stage II/III rectal cancer patients with a T3/T4 tumor is still unknown. Methods: Inclusion criteria in this multicenter phase II study as follows; Stage II/III (Ra/Rb) rectal cancer patients with a T3/T4 tumor, aged 20–80 years old, Eastern Cooperative Oncology Group performance status of 0–1. A planned patient population set is 50. The primary endpoint is preoperative response rate, and the secondary endpoints are histological effect, R0 resection rate, pCR rate, down-staging rate, neoadjuvant therapy completion rate, toxicity, the incidence of postoperative complications, and 3-year disease-free survival. Computed tomography was performed after 4 courses of mFOLFOX6. Patients with disease progression (DP) underwent resection of the primary lesion, while those without DP received another 2 courses of treatment. Treatment was discontinued when resection was not possible in patients with DP. Results: Registered patients from August 2011 to July 2013 totaled 53 (male n = 41, female n = 12) with a mean age of 60 (38–77). The number of patients with T3 and T4 tumors was 42 and 10, and patients at stages II and III were 10 and 42, respectively. One patient withdrew due to consent retraction. Median relative dose intensity of mFOLFOX6 therapy was 93.2% for L-OHP, 5-FU, and l-LV. Treatment completion was achieved in 96.2% and 84.6% for 4 and 6 courses, respectively, and withdrawal was due to patient's discretion, not adverse events. Preoperative response rate was 51%. Surgery was performed in 78.8% of patients. Serious (grade ≥3) toxicity included neutropenia (n = 5), leukopenia (n = 1), thrombocytopenia (n = 1), febrile neutropenia (n = 1), nausea (n = 1), vomiting (n = 1), and peripheral neuropathy (n = 2). The rates of R0 resection, pCR, and sphincter preservation were 91.0%, 10.3%, and 82.9%, respectively. The down staging rate was calculated as 2%. Postoperative complications included suture failure (n = 3), wound infection (n = 2), pneumonia (n = 1), and intestinal obstruction (n = 1). Conclusions: In a short period observation, neoadjuvant chemotherapy using mFOLFOX6 is a safe and efficacious treatment option for rectal cancer, especially locally advanced disease. Disclosure: All authors have declared no conflicts of interest.

371P - A Multicenter Phase Ii Trial of Nab-Paclitaxel in Combination with Capecitabine in Patients (Pts) with Her-2 Negative and Triple Negative Advanced Breast Cancer (Abc): an Interim Analysis

ABSTRACT Aim: ABC remains a therapeutic challenge in spite of the use of emerging new drugs. Nab-paclitaxel has better efficacy and no risk of hypersensitivity reactions when compared to paclitaxel. We studied the association of nab-paclitaxel and capecitabine in a novel schedule as I line treatment in a population of HER-2 negative and triple-negative ABC. An interim analysis was preplanned at 54 enrolled pts. Methods: Nab-paclitaxel 150 mg/m2 was administered day 1 and 8 out of 21 days in combination with capecitabine at 825 mg/m2 twice daily, day 1-14 out of 21 days as first line therapy for HER2 negative ABC. The primary endpoints of the study are response rate (RR) and progression-free survival (PFS), secondary endpoints are toxicity and overall survival (OS). Results: Sixty five pts were enrolled from 11 centers, 59 pts (90.8%) evaluable for RR and PFS (ITT), 58 pts evaluable (89.2%) for toxicity. Median age was 56 years (34-77), 21 (32.3%) pts had triple-negative ABC, 44 pts (67.7%) hormone receptor positive ABC. Median number of metastatic site was 2 (range 1-5), visceral disease was present in 48 pts (73.9%). Median number of cycles was 6 (range 1-8). CR were 4 (6.8%), PR 31 (52.5%), for an overall RR (ORR) of 59.3%. SD was observed in 15 pts (25.4%), PD in 9 pts (15.3%). In the subpopulation of triple negative ORR was 50%. Median PFS for all pts was 43 weeks (26-48), 25 weeks (11-37) in triple-negative pts. Hematological toxicity Grade 3/4 was seen in 12/3 pts (18.5%/4.6%) (neutropenia G3/4 10/1 pts (15.4%/1.5%) and febrile neutropenia 2 pts (3%), respectively). Non-hematological toxicity grade 3/4 was seen in 11/10 pts (17%/15.4%), particularly neuropathy G3/4 1/0 (1.5%/0%). Conclusions: Significant clinical activity and good tolerability was seen from the combination of nabpaclitaxel and capecitabine in HER-2 negative ABC. The study is ongoing, but data provide a basis to consider this regimen for further evaluation in phase III trials. Disclosure: All authors have declared no conflicts of interest.

Adjuvant sequential chemoradiation therapy in high-risk endometrial cancer: results of a prospective, multicenter phase-II study of the NOGGO (North-Eastern German Society of Gynaecological Oncology)

The management of high-risk endometrial cancer (HREC) remains controversial. We conducted a prospective multicenter phase-II clinical trial to evaluate an adjuvant chemotherapy (CT) with sequential radiotherapy (RT) in patients with HREC. Patients with HREC from 8 institutions in Germany were enrolled. After surgery, patients received four cycles of paclitaxel 175 mg/m² (P) and carboplatin AUC5 (C) (d1, q21d) and subsequent external pelvic radiation therapy (1.8 Gy/d, d1-5) at a total dose of 45 Gy with vaginal brachytherapy (3 × 5 Gy). Quality of life (QoL) was assessed using the EORTC-QLQ-C30 questionnaire. Primary endpoints were tolerability, toxicity and QoL. Progression-free survival (PFS) was defined as secondary endpoint. Thirty-five patients were enrolled from 2004 through 2008. Median follow-up was 24 months (range 3-24 months). All patients received 4 cycles of P and C and completed RT. Overall, grade 3/4 haematological toxicity was 25.6 %. Three cycles were delayed because of leukopenia. Grade 3/4 non-haematologic toxicities were rare (≤3 %). No overall change in QoL occurred during treatment. Two-year median PFS and OS rates were both 75.8 %. Adjuvant combination CT with P + C and sequential RT is well tolerated and a feasible regimen in patients with HREC. Subsequent phase-III trials are warranted.

10-year long-term survival (LTS) of induction chemotherapy with three cycles cisplatin/paclitaxel followed by concurrent chemoradiation cisplatin/etoposide/45 Gy (1.5 Gy bid) plus surgery in locally advanced non-small-cell lung cancer (NSCLC)—A multicenter phase-II trial (CISTAXOL)

BackgroundInduction chemoradiotherapy plus surgery remains an option to study in IIIA(N2) and selected IIIB NSCLC. Here we report ten-year long-term survival of a prospective multicenter German–French phase-II trial with trimodality. Patients and methodsMediastinoscopically proven IIIA(N2)/selected IIIB NSCLC received three cycles cisplatin (50mg/m2 day 1+8) and paclitaxel (175mg/m2d1) qd 22. Concurrent CTx/RTx followed: 45Gy (1.5Gy bid) with cisplatin 50mg/m2 day 2+9 and etoposide 100mg/m2 d 4–6. Surgery was planned three to five weeks after RTx. If evaluated inoperable/irresectable at the end of RTx, definitive RTx-boost (20Gy; 2Gy qd) followed. Here we report 10-year-LTS for this cohort. ResultsAll 64 patients were accrued 3/99 to 2/02. Patients characteristics: IIIA(N2)/IIIB 25/39; m/f 48/16; adeno/squamous/large-cell/adenosquamous/NOS 15/26/18/3/2; age: median 52.5 (range 33–69). 36 operated: R0 32/36 (89%); pCR 16/36 (44%). 10-year-LTS%; all 26.0; IIIA(N2) 37.1; IIIB 17.9; relevant prognostic factors (exploratory): pretreatment – histopathology (squamous/adeno) – age (<50/≥50) – Charlson-CI: 1/>1 – BMI (≥25/<25) – pack years smoking (≥10/<10); treatment-dependent – R0/no-R0. ConclusionsThis regimen achieves substantial LTS. Interestingly, adenocarcinomas, older patients, unfavorable comorbidity scores, higher BMI and light smokers demonstrate poor long-term outcome even with aggressive trimodality. This dataset defines the rationale for our ongoing randomized trial with surgery after induction therapy in IIIA(N2)/selected IIIB (ESPATÜ).

Azacitidine and donor lymphocyte infusions as first salvage therapy for relapse of AML or MDS after allogeneic stem cell transplantation

The combination of azacitidine and donor lymphocyte infusions (DLI) as first salvage therapy for relapse after allogeneic transplantation (allo-HSCT) was studied in 30 patients with acute myeloid leukemia (AML; n=28) or myelodysplastic syndromes (MDS; n=2) within a prospective single-arm multicenter phase-II trial. Treatment schedule contained up to eight cycles azacitidine (100 mg/m(2)/day, days 1-5, every 28 days) followed by DLI (from 1-5 × 10(6) to 1-5 × 10(8) CD3(+)cells/kg) after every second azacitidine cycle. A median of three courses azacitidine (range 1-8) were administered, and 22 patients (73%) received DLI. Overall response rate was 30%, including seven complete remissions (CRs, 23%) and two partial remissions (7%). Five patients remain in CR for a median of 777 days (range 461-888). Patients with MDS or AML with myelodysplasia-related changes were more likely to respond (P=0.011), and a lower blast count (P=0.039) as well as high-risk cytogenetics (P=0.035) correlated with the likelihood to achieve CR. Incidence of acute and chronic graft-versus-host disease was 37% and 17%, respectively. Neutropenia and thrombocytopenia grade III/IV occurred during 65% and 63% of treatment cycles, while infections were the most common grade III/IV non-hematological toxicity. Azacitidine and DLI as salvage therapy is safe, induces long-term remissions and may become an alternative for patients with AML or MDS relapsing after allo-HSCT.

A phase-I trial of pemetrexed plus carboplatin in recurrent ovarian cancer

Carboplatin-based combinations are established in platinum-sensitive recurrent ovarian cancer. To improve the therapeutic index, new platinum-based combinations are required. Pemetrexed is a multi-targeted antifolate inhibiting thymidylate synthase. The aim of this study was to determine the maximally tolerated dose (MTD) and dose-limiting toxicity (DLT) and to characterize toxicities of the combination of pemetrexed (Pem) and carboplatin (Cb). A standard three-patient cohort dose escalation was performed starting at Cb AUC-5 and Pem 500 mg/m(2). Patients with platinum-sensitive recurrent ovarian cancer were eligible. Two levels of Cb (AUC-5, 6) and five levels of Pem (500, 600, 700, 800, and 900 mg/m(2)) were evaluated. DLTs were based on cycle 1. Twenty patients were enrolled. The median age was 57.4 years (37.3-75.3) and the median platinum-free interval was 26.2 months (7.2-124.4). There was one DLT at dose level 3 in cycle one. No serious adverse events related to the study therapy were observed. The 20 patients completed 112 cycles of Cb (104 were planned) and 115 cycles of Pem (112 were planned). The maximum dose level of Cb AUC-6 and Pem 900 mg/m(2) was well tolerated. Response rates in 19 patients were: CR: 63.2%; PR: 21.1%; SD; 5.3%, PD: 10.5%. The combination carboplatin and pemetrexed is safe and well tolerated. A multicenter phase-II trial is currently underway.

High-Dose Chemotherapy and Autologous Stem-Cell Transplantation for Primary CNS Lymphoma: Updated Results from a Pilot and Phase II Study

Introduction: High-dose chemotherapy (HDT) and autologous stem-cell transplantation (ASCT) demonstrated high efficacy in the treatment of newly-diagnosed primary CNS lymphoma (PCNSL) in younger patients (pts.). A 5-year overall survival probability (OS) of 69% could be demonstrated in 30 pts within a phase-II trial on HDT and ASCT with consolidating whole-brain-irradiation (WBRT) (Illerhaus et al. JCO 2006). A subsequent pilot trial on HDT and ASCT without WBRT showed a 5-year OS of 77% (Illerhaus et al. Haematologica 2008). Here we give an update of our two different treatment regimens and future perspectives.Patients and Methods: Thirty pts. ≤65 years were treated within the phase II trial, chemotherapy (CHT) consisted of 3 cycles of high-dose methotrexate (MTX, 8 g/m2), 1 cycle of AraC (2× 3 g/m2) plus thiotepa (TT, 40 mg/m2) followed by rG-CSF and stem-cell-mobilization. Conditioning regimen included BCNU (400 mg/m2) and TT (2×5 mg/kgBW) followed by ASCT. Hyperfractionated WBRT (45 Gy, 2×1Gy/d) was administered as consolidation. In our subsequent pilot trial 13 pts. (age 38–67 years) were treated without consolidating WBRT; CHT was intensified with 4 cycles MTX 8g/m2, 2 cycles AraC (2× 3 g/m2) and TT (40 mg/m2). Dose escalated HDT included BCNU (400 mg/m2) and TT (4×5 mg/kgBW) followed by ASCT. WBRT was reserved for pts. not responding to CHT.Results: Median follow-up of the 30 pts. treated within our phase II trial was extended to 95 months (mo), the updated 5-year OS of all pts. is 66.6% and 82,3% of the subgroup of pts. who underwent HDT and ASCT (n=23), respectively. Three additional deaths occurred due to relapse (n=2) after 45 and 71 mo and due to comorbidity (n=1) after 103 mo. Five of 30 pts. developed severe leukoencephalopathy during follow-up. With a median follow-up of 35 mo in the 13 pts. treated within the pilot-phase without consolidating WBRT 3-year OS of all pts. is 77%. No further relapse or non-relapse mortality occurred in this pilot-group during. Most recent follow-up data will be presented in detail.Conclusion: Sequential systemic application of high-dose cytostatic agents followed by HDT+ASCT is highly effective as initial therapy for pts. with PCNSL. The restriction of WBRT to refractory disease shows similar OS rates and a decrease in neurotoxicity. In an ongoing multicenter phase-II trial immunotherapy with rituximab is combined with HDT and ASCT to further increase remission rates. A future randomized trial should be focused on the efficacy of consolidation with HDT supported by ASCT.

Induction chemotherapy with paclitaxel and cisplatin followed by radiotherapy for larynx organ preservation in advanced laryngeal and hypopharyngeal cancer offers moderate late toxicity outcome (DeLOS-I-trial)

A prospective multicenter phase-II trial (12 centers) was performed by the German larynx organ preservation group (DeLOS) to evaluate the effect of induction chemotherapy (ICHT) with paclitaxel/cisplatin (TP), followed by accelerated-hyperfractionated (concomitant boost) radiotherapy (RT) in responders. The trial was focused on larynx preservation, tumor control, survival, salvage surgery and late toxicity in patients with advanced larynx/hypopharynx carcinoma eligible for total laryngectomy (LE). Seventy-one patients (40 larynx, 87.5% St. III, IV; 31 hypopharynx, 93.4% St. III, IV) were enrolled into the study and treated with ICHT (200 mg/m(2) paclitaxel, 100 mg/m(2) cisplatin; day 1, 22) according to the DeLOS protocol. Patients with complete or partial tumor response proceeded to RT (69.9 Gy in 5.5 weeks). Non-responders received a LE followed by postoperative RT (56-70 Gy in 5.5-7 weeks). The response rate to ICHT for larynx cancer was 69.6% (7.1% complete, 62.5% partial response) and for hypopharyngeal cancer was 84.3% (6.9% complete, 77.4% partial response). Overall survival after 36 months was 60.3% (95% CI, 48.4-72.2%), after 42 months was 56.5% (95% CI, 44.2-68.8%). Laryngectomy-free survival was as follows: after 36 months, 43.0% (95% CI, 30.9-55.0%); after 42 months, 41.3% (95% CI, 29.3-53.3%). Both parameters did not show different outcomes after distinguishing larynx from hypopharynx. LE was indicated in 15 non-responders after ICHT. Five of the 15 non-responders refused the laryngectomy. Two of the five received RT instead and had no evidence of disease 42 months after RT. Late toxicity (dysphagia III, IV LENT SOMA score in laryngectomy-free survivors: after 6 months, 1.8%; 12 months, 11.4%; 18 months, 14.5%; 24 months, 8.1%; 36 months, 16%) and salvage surgery (4 pharyngocutaneous fistulas in 27 operations) were tolerable. In a large portion of patients eligible for LE, the larynx could be preserved with satisfying functional outcome. Good responders after ICHT had also a good general outcome with relatively rare severe late toxicities. Due to a slight increase of relevant late dysphagia, functional outcome regarding swallowing and tracheotomy free breathing should be more focused in future larynx organ preservation trials.

Multicenter phase-II trial of irinotecan plus oxaliplatin [IROX regimen] in patients with poor-prognosis cancer of unknown primary: a hellenic cooperative oncology group study

Cancer of unknown primary (CUP) lacks established therapy although it affects 3% of cancer patients. We evaluated the irinotecan-oxaliplatin combination (IROX regimen) in previously untreated patients with non-favorable subsets of unknown primary carcinomas. This was a multicenter phase-II trial. Protocol treatment consisted of oxaliplatin 80 mg/m(2) followed by irinotecan 160 mg/m(2) administered every 3 weeks. The primary end points were response rate and toxicity, and secondary end points were time to progression and survival. Forty-seven patients with liver, bone or multiple visceral metastases entered into the trial and received a median 6 chemotherapy cycles (1-11). The regimen was very well tolerated with one febrile neutropenia case and six cases with diarrhea grade 3 (16%). In intent-to-treat analysis the tumor response rate was 13% (95% CI = 4.8-25.7%) and 12 patients (27%, 95%CI 13.9-40.4%) had at least 4 months' duration of disease stabilization. The median time to progression was 2.7 months and the median survival was 9.5 months, with 40% of patients alive at 1 year. The IROX regimen demonstrated similar efficacy and a favorable toxicity profile compared to other more toxic chemotherapy combinations in patients with poor-prognosis CUP.

Biweekly pegylated liposomal doxorubicin in patients with relapsed ovarian cancer: results of a multicenter phase-II trial

BackgroundThe obvious benefit of pegylated liposomal doxorubicin (PLD) for tumour control in recurrent ovarian cancer is frequently offset by severe palmar-plantar erythrodysesthesia (PPE). There is evidence that dose reduction from 50 to 40 mg/m2 reduces the incidence of PPE without compromising cytotoxic activity. We set out to investigate whether biweekly application further improves the therapeutic index of PLD. Patients and methodsPatients with recurrent ovarian cancer after surgery and adjuvant chemotherapy with platinum and taxane compounds were eligible to participate in this multi-institutional phase II study. PLD was administered at a dose of 20 mg/m2 every two weeks. Eligible patients had ECOG performance status of ≤2, and sufficient organ function. We employed an optimized two-stage design to test the hypothesis that biweekly application of PLD reduces the frequency of grade III and IV PPE from 25% to 10%. Response and survival were addressed descriptively. ResultsBetween October 2001 and February 2004, 64 patients with median age of 59 (range 38–81) years were recruited onto this trial. We evaluated 553 (median 7, range 1–25) courses of PLD treatment. Most patients were in their third or fourth line of chemotherapy. PPE was noted in 30 patients (47.6%), but only three participants progressed to grade 3 severity (4.7%, 95% confidence interval 1.0–13.1%). Partial response, stable disease, and tumour progression were observed in 5, 13, and 24 patients, respectively. Median overall and progression-free survival were 18.2 (range, 1.4–34.0) and 4.3 (range 0.5–22.3) months. ConclusionsBiweekly PLD may reduce the incidence of PPE while retaining efficacy in relapsed ovarian cancer. Our data support the need for a randomized trial to strengthen these assumptions.