Non-hematological Toxicity Grade Research Articles

CTNI-32. A MULTICENTER PHASE 1 TRIAL OF TUCATINIB, TRASTUZUMAB, AND CAPECITABINE WITH STEREOTACTIC RADIOSURGERY IN PATIENTS WITH BRAIN METASTASES FROM HER2 POSITIVE BREAST CANCER (TUTOR)

Abstract BACKGROUND Nearly 20-40% of HER2+ breast cancer patients develop brain metastases (BMs), where stereotactic radiosurgery (SRS) is standard-for-care for local control. Tucatinib, an oral HER2-selective TKI, is safe and efficacious in HER2+ breast cancer in combination with capecitabine and trastuzumab. Synergism between these 3 drugs (TCT) and radiation may enhance DNA damage. This phase 1 trial aims to evaluate TCT plus SRS for HER2+ breast cancer BMs (BCBM). METHODS TUTOR is a pre-registered (NCT05553522), single-arm, multicenter, ongoing, phase 1 trial that aims to determine the safety and efficacy of TCT+SRS in HER2+ BCBM patients. Patients with age 18-80 years, ECOG score 0-2, normal organ function, and ≤10 newly-diagnosed BMs are being enrolled at six US centers. Any number of prior systemic therapies are allowed, except tucatinib and capecitabine. Key exclusion criteria include leptomeningeal metastases, intra-tumoral or peri-tumoral hemorrhage, and BMs ≤5 mm of optic chiasm/nerve. Primary endpoint is maximum tolerated dose (MTD) of tucatinib, in this 3 + 3 de-escalation study starting at dose level (DL) 300 mg BID. DL-1 is 250 mg BID, and DL-2 is 200 mg BID. Secondary endpoints include efficacy as determined by response rate, intracranial progression-free survival (PFS), extracranial PFS, and overall survival. Neurocognitive outcomes are assessed using Hopkins Verbal Learning, Controlled Oral Word Association, Trail Making, and Grooved Pegboard Tests. Toxicities are assessed using CTCAE v5.0. Quality of life is assessed using Functional Assessment of Cancer Therapy with Brain Tumor module. Patients are administered tucatinib with SRS as per treating radiation oncologist, followed by tucatinib for two weeks, i.e. dose-limiting toxicity (DLT) period, followed by TCT until progression or intolerable toxicity. DLTs are defined by Grade 3 or 4 thrombocytopenia, grade 4 anemia, grade 4 neutropenia lasting >7 days, febrile neutropenia, and any non-hematologic toxicity of grade ≥3 (excluding alopecia). Cohort expansion at MTD to 40 patients is planned. Patient enrollment started in February 2023 and remains ongoing.

Comparison of the treatment outcomes of different neoadjuvant chemoradiotherapy regimens for resectable locally advanced esophageal cancer

BackgroundNeoadjuvant chemoradiotherapy (nCRT) followed by radical esophagectomy is the standard treatment for locally advanced esophageal squamous cell cancer (LA-ESCC). However, various nCRT regimens have been used, and their comparative efficacy and safety remain unclear. MethodsPatients with histologically confirmed LA-ESCC who underwent nCRT followed by radical esophagectomy between January 2016 and February 2022 were enrolled in this study. Of note, 3 different nCRT regimens were retrospectively compared: conventional radiotherapy (RT) + cisplatin/5-fluorouracil (FP) (Conv-FP), hypofractionated RT + FP (Hypo-FP), and regimens from the ChemoRadiotherapy for Oesophageal cancer followed by Surgery Study (CROSS) trial (CROSS). The overall survival (OS), pathologic complete response (pCR), toxicity, and treatment compliance rates were analyzed. ResultsAmong the 600 patients, 225 received Conv-FP, 255 received Hypo-FP, and 120 received the CROSS regimen. The OS rates at 1 year were 78.7%, 83.9%, and 88.1% in the Conv-FP, Hypo-FP, and CROSS groups, respectively (P < .001). The pCR rates were 30.6%, 33.9%, and 35.0%, respectively (P = .653). The overall incidence of grade 3 toxicities was 10.2%. Hematologic and nonhematologic toxicities of grade ≥ 3 were observed in 8.4% and 11.4%, 0% and 7.6%, and 5.5% and 0.8% in the Conv-FP, Hypo-FP, and CROSS groups, respectively (P = .002 and P = .030). Weight loss of > 5% was observed in 44.0%, 51.4%, and 32.5% in the Conv-FP, Hypo-FP, and CROSS groups, respectively (P < .001). In the multivariate analysis, clinical T stage (P = .004), N stage (P = .012), FP chemotherapy regimen (P = .013), surgical resection (P < .001), hematologic toxicity (P = .001), and weight loss (P = .004) were significantly associated with poor OS. ConclusionThe choice of nCRT regimen did not significantly affect the pCR rates in patients with LA-ESCC. However, the CROSS regimen demonstrated better OS and lower toxicity, suggesting that it may be the optimal treatment option among the groups.

N9: Pilot study of novel shortened induction for high-risk neuroblastoma.

10052 Background: N9 induction for high-risk neuroblastoma was designed to limit non-hematological toxicity (especially ototoxicity) and to prevent relapse in the central nervous system (CNS). N9 builds on 2 novel regimens: high-dose cyclophosphamide-topotecan-vincristine (CTV) and ifosfamide-carboplatin-etoposide (ICE), each with good penetration across the blood-brain barrier. Methods: N9 is a pilot study (Clinicaltrials.gov.NCT04947501) to assess feasibility and safety. Secondary/exploratory objectives include response, collection of peripheral blood stem cells (PBSCs; ≥5x106/kg CD34(+) cells sufficient for ≥2 rescues), tumor resection, and assessment of central nervous system relapse. Early stopping rules centered on excessive delay in timing of chemotherapy. Eligibility criteria included age &gt;1-to-&lt;13 years; 1 prior chemotherapy cycle was allowed. CTCAE Version 5.0 and International Neuroblastoma Response Criteria are used.N9 comprises 4 cycles of chemotherapy. Cycles start after absolute neutrophil count is &gt;500/μL, platelets &gt;100,000/μL, and non-hematologic toxicities grade ≤2. Intervals of 21-28 days between start of cycles are foreseen. PBSC collection and surgery follow &gt;3 cycles. Cycles #1 and #4 (CTV): cyclophosphamide 70mg/kg/day, days 1-2, topotecan 2mg/m2/day, days 1-4, and vincristine 0.067mg/kg, day 1. Cycle #2 (ICE): ifosfamide 1500mg/m2/day, days 1-5, carboplatin 400mg/m2/day, days 1-2, and etoposide 100mg/m2/day, days 1-5. Cycle #3: cyclophosphamide (as in CTV) and 72-hr infusions of doxorubicin 75mg/m2 and vincristine 0.067mg/kg. Results: The target number of 15 patients were enrolled: 10/2021-9/2023; age 1.5–9.8 (median 3.3) years; 14 stage M, 1 stage L2; and 10 post-1 cycle of other chemotherapy. They completed N9 without undue toxicity: all cycles started on time, organ functions remained intact, 11/11 patients tested had no ototoxicity, and acute toxicities were typical for myelosuppression (including uncomplicated fever/neutropenia). Responses were complete (n=6), partial (n=5), and stable disease (n=4). The target number of PBSCs was collected in 12 patients (9-75, median 14 x106/kg CD34(+) cells), 4x106/kg in 2 patients, and pending in 1. All patients had gross total resections of the primary tumor. Post-N9, patients did not undergo transplant, but proceeded to immunotherapy (naxitamab) or chemoimmunotherapy (naxitamab+irinotecan-temozolomide). Of 9 with residual disease post-N9, 7 achieved CR (median of 5.6 months from study entry) and 1 achieved metabolic CR (16 months), though 3 subsequently relapsed (no CNS). Conclusions: N9 shows promise for reducing chemotherapy and long-term toxicity. Less chemotherapy without compromising survival is a realistic goal by virtue of the advances with anti-GD2 monoclonal antibodies which, in combination with GM-CSF+low-dose chemotherapy, are highly effective against chemo-resistant disease in bone/bone marrow. Clinical trial information: NCT04947501 .

Effect of nivolumab combined with definitive chemoradiotherapy on response rate for esophageal cancer: An immune active intrinsic subtype could be its biomarker—The NOBEL trial.

4068 Background: The usefulness of combined therapy with immune checkpoint inhibitors (ICI) and chemoradiotherapy (CRT) and its potential biomarker of treatment efficacy for esophageal cancer remains unclear. We investigated the safety, efficacy, and associated biomarkers of combined therapy with ICI and definitive CRT in operable and inoperable esophageal squamous cell carcinoma (ESCC). Methods: This prospective single-arm phase 2 trial was performed at five hospitals in Japan. Patients aged 20–75 years with histologically confirmed ESCC, an ECOG PS score of 0 or 1, and adequate organ and bone marrow functions were eligible. Inoperable patients did not have distant organ metastasis. Patients did not receive any chemotherapy or surgical resection as an initial therapy. Concurrent radiotherapy (50.4 Gy/28 fractions to the primary lesion and 41.4 Gy/23 fractions to the regional LN area) consisted of 4 courses of CF (cisplatin, 75 mg/m2/day, day 1; 5-fluorouracil, 1000 mg/m2/day, days 1–4) plus nivolumab (240 mg/m2/day, every 2 weeks for up to 1 year). The primary endpoint was safety. The incidence rates of nonhematological toxicity grade ≥ 4 and pneumonitis grade ≥ 3 were ≤10% and ≤15%, respectively. The secondary endpoints included overall survival (OS), progression-free survival (PFS), complete response (CR) rate, and time to esophagectomy-free survival (EFS). Sixty patients were to be accrued, but the trial enrollment was terminated because of slow accrual. This trial was registered as jRCT1091220408. Results: Between January 2019 and September 2021, 42 patients were enrolled. Twenty-five patients had operable disease and 16 had inoperable disease. Two patients (4.8%) experienced grade 3 pneumonitis, suggesting that the primary endpoint was met. The median relative dose intensity of nivolumab was 92.4%. One-year OS, PFS, and EFS rates in all cases were 92.7%, 65.4%, and 78.0%, respectively. One-year OS, PFS, and EFS rates in operable and inoperable cases were 100%, 79.6%, and 84.0% and 81.3%, 43.8%, and 68.8%, respectively. The CR and objective response rates were 73.2% (95% confidence interval [CI]: 58.1%–84.3%) and 87.8% (95% CI: 74.5%–94.7%), respectively. The CR rates in operable and inoperable cases were 84% (95% CI: 65.3%–93.6%) and 56.3% (95% CI: 33.2%–76.9%), respectively. Immune high-active intrinsic subtype before treatment (n=4) with an expression score &gt; 80 of 51 immune-related genes showed a high CR rate (100%, n=4), whereas the immune low-active intrinsic subtype (n=37) with an expression score &lt; 80 showed a relatively high CR rate (70%). Conclusions: Nivolumab combined with definitive CRT provided encouraging efficacy and acceptable toxicity in patients with ESCC. Immune high-active intrinsic subtype before treatment has the potential to predict a high CR rate for this combination treatment. Clinical trial information: jRCT1091220408 .

Preliminary results of surgical treatment and neoadjuvant chemotherapy in upper rectal cancer

Introduction: There is a lack of information on the role of neoadjuvant chemotherapy in upper rectal cancer. The aim of our research was to investigate the role of neoadjuvant chemotherapy in upper rectal cancer treatment.Materials and methods: We conducted a retrospective cohort multicenter study to analyze the medical records of patients with upper rectal cancer from 2007 to 2020 obtained from the archive of Research Institute FSBI «N. N. Blokhin Cancer Research Center» of the Ministry of Health of Russia, A. N. Ryzhikh National Medical Research Centre for Coloproctology, Stavropol regional Clinical oncological Dispensary and Kaliningrad oncological Center. All patients were divided into 2 groups: group 1 included patients who underwent neoadjuvant chemotherapy with CAPOX as the first treatment step, and group 2 included patients who underwent upfront surgery. Primary endpoint was 3‑year disease-free survival (DFS) rate. We also estimated the pathological complete response (pCR) rate, treatment toxicity, postoperative morbidity rate (Clavien – Dindo), degree of tumor regression, local recurrence rate, distant metastases rate, 3‑year overall survival (OS) and the neoadjuvant chemotherapy completion rate.Results: 118 patients were included in the neoadjuvant chemotherapy group and 103 patients — in the surgery group. Study groups were well balanced and comparable for gender, the ASA status and the tumor differentiation grade. More patients in the neoadjuvant chemotherapy group had clinically positive lymph nodes (p = 0.002). Median follow-up period was 36 months. There were no significant differences in 3‑year OS and DFS. The local recurrence rate was 3.9 % in the surgery group versus 0 % in the neoadjuvant chemotherapy group (p = 0.046). There were no significant differences between study groups in the distant metastases rate (p = 0.293). Sixteen (13.6 %) patients had a pCR after neoadjuvant chemotherapy. The neoadjuvant chemotherapy completion rate was 91.5 %. The hematological toxicity grade 3–4 was observed in 3.3 % (4 patients), the non-hematological toxicity grade 3–4 in 3.3 % (4 patients).Conclusion: NACT has an acceptable toxicity profile, does not impede oncological treatment results, and can be used in a selected group of patients for early systemic control.

Alternating Gemcitabine/Nab-Paclitaxel (GA) and 5-FU/Leucovorin/Irinotecan (FOLFIRI) as First-Line Treatment for De Novo Metastatic Pancreatic Cancer (MPC): Safety and Effect

Background: Both gemcitabine- and 5-fluorouracil (5-FU)-based chemotherapy regimens have demonstrated efficacy in metastatic pancreatic cancer (MPC). Alternating these regimens may reduce toxicity, slow resistant cancer biology emergence, and provide a platform for the addition of other therapeutic agents. Alternating gemcitabine/nab-paclitaxel (GA) and 5-FU/leucovorin/irinotecan (FOLFIRI) in MPC has previously been reported at our own institution and elsewhere. An extension of our institutional observations is reported here. Methods: Patient eligibility required the following: biopsy-proven de novo MPC, no prior evidence of disease on CT, ECOG performance status (PS) ≤ 2, and bi-dimensionally measurable disease. Treatment (Tx) entailed gemcitabine 1000 mg/m2 and nab-paclitaxel 125 mg/m2 1, (8), 15 alternating every 8 weeks (2 cycles) with FOLFIRI using standard dosing. Patients were radiographically re-staged every 8 weeks. Tx spanned up to 12 cycles. Tx thereafter was decided following patient/physician discussion. Results: Median overall survival (mOS) was 13.2 months (95% CI 10.9–16.5 months). Median progression-free survival (mPFS) was 8.5 months (95% CI, 7.1–9.9). The 6-, 12-, 18-, and 24-month OS rates were 88%, 54%, 36%, and 20%, respectively. The disease control rate at 16 weeks was 83% (37% PR, 46% SD). Hematologic toxicity grade ≥ 3 included 9.3% anemia, 10.2% neutropenia, and 4.6% thrombocytopenia. Neutrophil growth factors were not used in this cohort. Non-hematologic toxicities grade ≥ 3 included neuropathy 0.9%, nausea/vomiting 0.9%, and diarrhea 0.9%. No patients experienced mucositis on this regimen. Conclusions: Alternating GA/FOLFIRI in MPC has a favorable toxicity profile in comparison to current standard regimens. Median OS was at least competitive with standard regimens, and longer-term (18 and 24 months) OS seemed particularly encouraging. Treatment for ≥48 weeks and ECOG PS of zero at the time of treatment initiation were prognostically significant. Further investigation using this regimen including randomized comparisons, the incorporation of molecular data, and use of additional agents is merited.

CTNI-08. TUCATINIB, TRASTUZUMAB, AND CAPECITABINE WITH STEREOTACTIC RADIOSURGERY IN PATIENTS WITH BRAIN METASTASES FROM HER-2 POSITIVE BREAST CANCER (TUTOR): A MULTICENTER PHASE 1 CLINICAL TRIAL

Abstract BACKGROUND 20-40% of HER-2-positive breast cancer patients develop brain metastases (BMs), which are frequently tackled with stereotactic radiosurgery (SRS). Tucatinib, an oral HER-2 selective tyrosine kinase inhibitor (TKI), has demonstrated efficacy for HER-2-positive breast cancer in combination with capecitabine and trastuzumab. We hypothesize that a combinatorial approach for HER-2 positive breast cancer BMs (BCBM) will lead to better long-term control of BMs and systemic disease. METHODS This is an in-progress, prospective, single-arm, multicenter, phase 1 clinical trial that aims to determine the safety of combination of tucatinib, capecitabine, and trastuzumab with SRS in patients with HER-2 positive BCBM. Patients with age 18-80 years, ECOG 0-2, normal organ function, and up to 10 newly-diagnosed BMs are enrolled at six US centers. Any number of prior systemic therapies are allowed, except tucatinib and capecitabine. The primary endpoint of the study is the maximum tolerated dose (MTD) of tucatinib with SRS. This de-escalation study starts tucatinib at a dose level of 300 mg BID. Dose level -1 is 250 mg BID and level -2 is 200 mg BID. Upto 40 patients will be enrolled based on a 3 + 3 design. We plan to expand the cohort at MTD to 40 patients to assess the safety and efficacy of the combination. Secondary endpoints include efficacy as determined by response rate, intracranial PFS, extracranial PFS, and overall survival. Patients are administered oral tucatinib with SRS, followed by oral tucatinib for two weeks which is the dose-limiting toxicity (DLT) period. This is followed by tucatinib, trastuzumab, and capecitabine until progression or intolerable toxicity. DLTs are defined by Grade 3 or 4 thrombocytopenia, grade 4 anemia, grade 4 neutropenia lasting more than seven days, febrile neutropenia, and any non-hematologic toxicity of grade 3 or greater (excluding alopecia). The trial started enrollment in February 2023. Trial Information: NCT05553522.

JS06.5.A TUCATINIB, TRASTUZUMAB, AND CAPECITABINE WITH STEREOTACTIC RADIOSURGERY IN PATIENTS WITH BRAIN METASTASES FROM HER-2 POSITIVE BREAST CANCER (TUTOR): A MULTICENTER PHASE 1 CLINICAL TRIAL

Abstract BACKGROUND 20-40% of HER-2-positive breast cancer patients develop brain metastases (BMs), for which stereotactic radiosurgery (SRS) is used for local disease control. Tucatinib, an oral HER-2-selective tyrosine kinase inhibitor (TKI), has been demonstrated to be safe and efficacious in HER-2-positive breast cancer in combination with capecitabine and trastuzumab. The synergism between these three drugs and radiation may potentially enhance DNA damage, causing increased apoptosis. We hypothesize that this 3-drug therapy, in combination with SRS in patients with HER-2 positive breast cancer BM (BCBM), may be safe and provide superior long-term control of intracranial and systemic disease. METHODS This is a prospective, single-arm, multicenter, ongoing, phase 1 clinical trial that aims to determine the safety of the combination therapy in patients with HER-2 positive BCBM. Patients aged 18-80 years, ECOG score 0-2, normal organ function, and up to 10 newly-diagnosed BMs are being enrolled at six centers in the US. Any number of prior systemic therapies are allowed, except tucatinib and capecitabine. Key exclusion criteria include leptomeningeal metastases documented by MRI or CSF evaluation, evidence of intra-tumoral or peri-tumoral hemorrhage, and BMs within 5 mm of the optic chiasm/nerve. The primary study endpoint is maximum tolerated dose (MTD) of tucatinib with SRS. This de-escalation study starts tucatinib at a dose level of 300 mg twice daily (BID). Dose level -1 is 250 mg BID, and dose level -2 is 200 mg BID. Up to 40 patients will be enrolled in this study based on a 3 + 3 design. We plan to expand the cohort at MTD to total of 40 patients to assess the safety and efficacy of drug combination. Secondary endpoints include efficacy as determined by response rate, intracranial progression-free survival (PFS), extracranial PFS, and overall survival. Neurocognitive outcomes are being assessed by Hopkins Verbal Learning Test, Controlled Oral Word Association, Trail Making Test Part A and B, and Grooved Pegboard Test. Acute and late toxicity is assessed using CTCAE v5.0. Quality of life is assessed by Functional Assessment of Cancer Therapy, including Brain Tumor module (FACT-Br). Patients are administered oral tucatinib with SRS as per the treating radiation oncologist, followed by oral tucatinib for two weeks which is the dose-limiting toxicity (DLT) period. This is followed by tucatinib, trastuzumab, and capecitabine until progression or intolerable toxicity. DLTs are defined by Grade 3 or 4 thrombocytopenia, grade 4 anemia, grade 4 neutropenia lasting more than seven days, febrile neutropenia, and any non-hematologic toxicity of grade 3 or greater (excluding alopecia). RESULTS Patient enrollment started in February 2023. CONCLUSION Findings from this trial will demonstrate the safety and efficacy of this combination treatment in BCBM (Clinical Trial Information: NCT05553522).

Phase II feasibility study of adjuvant chemotherapy with docetaxel/cisplatin/S-1 followed by S-1 for stage III gastric cancer

BackgroundThis study aimed to evaluate the feasibility, safety, and efficacy of postoperative adjuvant chemotherapy with docetaxel/cisplatin/S-1 (DCS) following S-1 therapy in patients with stage III gastric cancer after curative gastrectomy.MethodsPatients with stage III gastric cancer who underwent D2 gastrectomy were enrolled. Adjuvant chemotherapy was initiated within 8 weeks of gastrectomy. The first cycle of chemotherapy consisted of S-1 monotherapy (day 1–14), followed by a 7-day rest period. Cycles 2 and 3 consisted of the following: S-1 (day 1–14) administration, followed by a 14-day rest period, and an intravenous infusion of cisplatin and docetaxel on days 1 and 15. After two cycles, S-1 was administered for up to 1 year.ResultsThirty patients were enrolled between 2014 and 2017. Febrile neutropenia of grade 3 or higher was the most common hematological toxicity with 4 patients (13.3%). Other hematological toxicities of grade 3 or higher were as follows: neutropenia in 3 (10.0%), leukopenia in 3 (10.0%), and anemia in 2 (6.7%) patients. Most frequent non-hematological toxicity of grade 3 was anorexia (n = 4, 13.3%) and general fatigue (n = 3, 10.0%); no grade 4 non-hematological toxicities were observed. Twenty-five patients (83.3%) completed two cycles of DCS treatment and 18 (60.0%) completed subsequent S-1 treatment for 1 year. The relative dose intensity of docetaxel and cisplatin was 0.86 and that of S-1 was 0.88.ConclusionThe DCS regimen can be acceptable as an adjuvant chemotherapy and offers an effective postoperative treatment option for stage III gastric cancer patients.Trial registration numberUMIN000012785.Date of registry08/01/2014.

Treatment of Relapse of MDS, AML and CMML after Allogeneic Blood Stem Cell Transplantation with Azacitidine, Lenalidomide and Donor Lymphocyte Infusions - Results from the First Interim Analysis of the Azalena-Trial (NCT02472691)

Background:Azacitidine (Aza) and donor lymphocyte infusions have become a standard treatment of myeloid malignancies relapsing after allo-SCT. Studies so far showed response rates ranging from 10% to 75% following treatment with Aza with or without donor lymphocyte infusions (DLI) and particularly patients (pts) with MDS and AML with low disease burden seem to benefit most. Lenalidomide (Len), due to its immunomodulatory and antileukemic properties, may act synergistically with Aza and DLI.Design/Methods:We initiated a prospective, multicenter, single-arm phase-II trial combining Aza, Len and DLI in patients with MDS, AML or CMML as first salvage treatment for relapse after allo-SCT. Pts were envisaged to receive up to 8 cycles Aza (75 mg/m2/d d1-7, every 28 days) and 3 DLI with increasing dosages (0.5×106 - 1.5×107 cells/kg) after cycles 4, 6 and 8. Concomitantly, eight cycles of Len were administered with a daily dose of 2.5 mg for the first 21 days of a 28 day-cycle each.To cope with the potential risk of GvHD induction by Len after allo-SCT the primary endpoint is safety and the study incorporates two interim analyses scheduled after the first 10 and 20 patients respectively. If no dose limiting toxicity (DLT) defined as steroid refractory acute GvHD grade III/IV, chronic GvHD NIH score severe or any unexpected hematologic and non-hematological toxicity grade ≥ III is observed in more than 3 patients in the first interim analysis, the dose of Len will be increased to 5 mg/day for the next 10 patients. Otherwise the study will be stopped.Results:Here we present the results of the first interim analysis (data lock February 20th 2017), which includes 10 patients (median age: 64 years, range 43 to 73) who experienced molecular (70%) or hematological (30%) relapse of MDS (70%), AML (20%) or CMML (10%) after median of 275 days (range: 91 to 937) following allo-SCT. So far, these 10 patients have received a total of 54 cycles of Len corresponding to median of 7 cycles per patient (range: 1 to 8). In addition, patients received a median of 7 courses of Aza (range 1-8) and 7 of 10 pts (70%) received at least one DLI (median: 1, range: 0-5).No DLT was observed. Two patients either developed acute GvHD (20%, overall grade I and III) and chronic GvHD (20%, NIH score mild and moderate). Treatment-associated neutropenia, thrombocytopenia or anemia CTC grade III/IV occurred in 75%, 50% and 0% of the patients, respectively. Common adverse events were gastrointestinal side effects, elevation of liver enzymes as well as infections. Nevertheless, during the treatment period only 2 patients needed to be hospitalized. Although efficacy was not the major scope of this first interim analysis, of 7 evaluable patients (early drop-out of 3 patients) 4 (57%) achieved complete remission and 1 patient (14%) achieved partial remission resulting in overall response rate of 71%.Conclusion:This interim-analysis shows that the combination of Aza, Len (21x2.5 mg/cycle) and DLI as first salvage therapy for relapse after allo-SCT is safe and feasible and not associated with excess GvHD. According to the protocol, the dose of Lena will now be increased to 21x5 mg/cycle for the next 10 patients. Furthermore, due to the label extension of Aza, the inclusion criteria will also be amended to AML patients with >30% BM blasts. DisclosuresSchroeder:Celgene: Consultancy, Honoraria, Other: travel support. Rautenberg:Celgene: Other: travel support. Scheid:BMS: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Nachtkamp:Celgene: Other: Travel Support. Germing:Janssen: Honoraria; Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Kröger:RIEMSER Pharma: Research Funding; Novartis AG: Research Funding; Amgen Inc.: Speakers Bureau; Janssen Global Services, LLC: Speakers Bureau; Neovii Pharmaceuticals AG: Speakers Bureau; Novartis AG: Speakers Bureau; Sanofi: Speakers Bureau. Kobbe:Celgene: Other: Advisory Board, Research Funding.

Depth of Response to Isatuximab, Carfilzomib, Lenalidomide and Dexamethasone (Isa-KRd) in Front-Line Treatment of High-Risk Multiple Myeloma: Interim Analysis of the GMMG-CONCEPT Trial

Depth of Response to Isatuximab, Carfilzomib, Lenalidomide and Dexamethasone (Isa-KRd) in Front-Line Treatment of High-Risk Multiple Myeloma: Interim Analysis of the GMMG-CONCEPT Trial

Depth of response to isatuximab, carfilzomib, lenalidomide, and dexamethasone (Isa-KRd) in front-line treatment of high-risk multiple myeloma: Interim analysis of the GMMG-CONCEPT trial.

8508 Background: High-risk (HR) multiple myeloma (MM) still has a significant impaired prognostic outcome. Addition of CD38 monoclonal antibodies to standard-of-care regimens significantly improved response rates and depth of response in newly diagnosed (ND) and relapsed/refractory MM patients (pts). Here, we report the prespecified end of induction interim analysis (IA) of the investigator-initiated GMMG-CONCEPT trial (NCT03104842), evaluating the quadruplet regimen isatuximab plus carfilzomib, lenalidomide and dexamethasone (Isa-KRd) in HR NDMM pts. Methods: 153 pts with HR NDMM are planned to be included into the trial. HR MM is defined by the presence of del17p or t(4;14) or t(14;16) or &gt; 3 copies 1q21 and ISS 2 or 3 stage disease. Pts receive 6 cycles of Isa-KRd induction, 4 cycles of Isa-KRd consolidation and Isa-KR maintenance. Transplant eligible pts (arm A) undergo high-dose therapy. Transplant ineligible pts (arm B) receive 2 additional cycles of Isa-KRd induction. The primary endpoint is MRD negativity measured by next-generation flow after consolidation. This IA reports on overall response rates (ORR) after induction. Additional MRD analysis will be presented. Results: 50 pts (46 arm A, 4 arm B) were included in the IA population for ORR. HR MM was defined by del17p in 52%, t(4;14) in 38%, t(14;16) in 12% and &gt; 3 copies 1q21 in 42%. 39/46 pts in arm A and 4/4 pts in arm B completed induction treatment. ORR was 100%, with 5 pts (10.0%) showing partial response (PR), 22 (44.0%; including 4 in arm B) very good partial response (VGPR) and 23 (46.0 %) complete response (CR). Median stem cell yield was 6.6 × 106CD34+ cells/kg. Grade 3/4 treatment-emergent adverse events (≥ 10%) with Isa-KRd included neutropenia (34.0%), leukopenia (26.0%) and thrombocytopenia (14.0%). Main non-hematologic toxicities grade 3/4 were hypertension (12.0%) and infection (8.0%). Conclusions: To the best of our knowledge, we report for the first time on a trial investigating solely HR NDMM and Isa-KRd quadruplet treatment. Isa-KRd induction induces deep responses in HR MM pts. The overall safety profile of Isa-KRd is expected and consistent with previous reports. The study is ongoing, with pts continuing to be included. Clinical trial information: 03104842 .

Final Results of Phase 2 Clinical Trial of LCL161, a Novel Oral SMAC Mimetic/IAP Antagonist, for Patients with Intermediate to High Risk Myelofibrosis

Final Results of Phase 2 Clinical Trial of LCL161, a Novel Oral SMAC Mimetic/IAP Antagonist, for Patients with Intermediate to High Risk Myelofibrosis

513P - Phase II study of vitamin B12 and folate supplementation for patients undergoing chemotherapy with pemetrexed

BackgroundTo assess the safety and efficacy of vitamin B12 and folic acid starting 24 to 48 hours before the chemotherapy including pemetrexed (PEM). MethodsPatients with advanced non-squamous non-small cell lung cancer or malignant pleural mesothelioma diagnosed and scheduled for chemotherapy including PEM were enrolled. Vitamin B12 and folic acid were administered 24-48 hours before the initiation of chemotherapy and we assessed the safety and efficacy of chemotherapy prospectively. As hematologic toxicity by this method has been confirmed in previous study, the primary endpoint was the incidence of non-hematologic toxicity grade 3 or worse during treatment and the secondary endpoint was hematologic toxicity, response rate, progression-free survival, and homocysteine concentration. Results103 patients were enrolled. The median age was 67 years (range 31-84 years), the gender was 59 male and 44 female and PS 0/1/2 were 33/69/1. Histological types were 96 cases of advanced non-squamous non-small cell lung cancer and 7 cases of malignant pleural mesothelioma. The regimens were CDDP+PEM 80 cases, PEM single agent 11 cases, CBDCA+PEM 7 cases, CDDP+PEM+BEV 3 cases, CBDCA+PEM+BEV 2 cases. The incidence of nonhematologic toxicity at grade 3 or worse was 11 cases (10.7%), achieving the primary endpoint. The incidence of hematologic toxicity at grade 3 or worse was 25 cases (24.3%). The response rate for CDDP+PEM in advanced non-squamous non-small cell lung cancer was 51.4% and a median progression-free survival was 4.8 months. ConclusionsThe method of administering vitamin B12 and folic acid 24 to 48 hours before initiation of chemotherapy including PEM was safe and there was no problem in efficacy. Clinical trial identificationUMIN000010570. Legal entity responsible for the studyYukio Hosomi. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Efficacy and safety of nivolumab in first-line or further treatment of advanced metastatic biliary tract cancer.

315 Background: PD-1 inhibitors have improved efficacy in many cancers. There are few report of nivolumab for metastatic biliary tract cancer (MBTC). This study reviewed the efficacy and safety of nivolumab for MBTC to improve efficacy and survival. Methods: Thirty patients with MBTC were voluntarily treated with non-clinical nivolumab at the PLA General Hospital. Nivolumab 200 mg or 180 mg was administered according to patient tolerance. Progression free survival (PFS), overall survival (OS) was evaluated by kaplan-meier and univariate analysis were carried out among clinical characteristics. Objective response rates (ORR), disease control rates (DCR), and treatment-related adverse events (AEs) were also evaluated. Results: The median treatment cycle is 4 cycles. One case was complete response (CR), 5 cases partial response (PR), 12 cases stable (SD). ORR was 20%, DCR was 60%. PFS was 3.1m (95% CI: 2.13~4.06 months). The AEs of nivolumab monothrapy were fatigue (3 cases), fever (2 cases), hypothyroidism (1 case), skin reaction (1 case). Nivolumab combined with chemotherapy related 1-2 hematologic toxicity were leukopenia (5 cases), thrombocytopenia (2 cases), and grade 3-4 were leukopenia (3 cases). Non-hematologic toxicity grade 1-2 were nausea and vomiting (4 cases), fatigue (4 cases), fever (3 cases), peripheral neurotoxicity (3 cases), and hypothyroidism (1 case). Univariate analysis showed that PFS was 4.20m in patients older than 53 years, slightly higher than those younger than 53 years (3.0 m, P = 0.047). PFS of nivolumab combined with chemotherapy was statistically significant compared with nivolumab monothrapy (4.1 m vs 2.3 m, p = 0.031). Patients with metastatic number &gt; 2 had a shorter PFS than those &lt; 2 (1.4 m vs 4.1 m, P = 0.05). PD-L1 expression positive have no better PFS compared with PD-L1 negative (3.6 m vs 3.1 m , p = 0.801). Multivariate analysis show nivolumab combined with chemotherapy was only independent factor for longer PFS (HR: 0.432, P &lt; 0.05). Conclusions: the safety of nivolumab in MBTC is controllable. Subgroup analysis suggests that further selection of superior populations is needed and sample size need to be expanded to improve the efficacy of nivolumab in MBTC.

Efficacy and safety of nivolumab for metastatic biliary tract cancer.

ObjectivePD-1 inhibitors have improved efficacy in many cancers. There are currently no reports of the use of PD-1 inhibitors, such as nivolumab, for metastatic biliary tract cancer (mBTC). This study reviewed the efficacy and safety of nivolumab for mBTC with the aim of exploring ways to improve efficacy and survival.MethodsThirty patients with mBTC were voluntarily treated with nivolumab at the PLA General Hospital. Nivolumab 3 mg/kg was administered. Progression-free survival (PFS) and overall survival were evaluated by Kaplan–Meier and univariate and multivariate analyses were carried out for clinical characteristics. Objective response rate (ORR), disease control rate (DCR), and treatment-related adverse events (AEs) were also evaluated.ResultsThe median treatment cycle is four cycles. One case was complete response, 5 cases partial response, 12 cases stable, and 12 cases progression. ORR was 20%, DCR was 60%, and PFS was 3.1 months (95% CI: 2.13–4.06). The AEs of nivolumab monotherapy were fatigue (three cases), fever (two cases), hypothyroidism (one case), skin reaction (one case), and liver injury (one case). Nivolumab combined with chemotherapy related grade 1–2 hematologic toxicity were leukopenia (five cases) and thrombocytopenia (two cases), and grade 3–4 were leukopenia (three cases). Non-hematologic toxicity grade 1–2 were nausea and vomiting (four cases), fatigue (four cases), fever (three cases), peripheral neurotoxicity (three cases), and hypothyroidism (one case). Univariate analysis showed that PFS of nivolumab combined with chemotherapy was statistically significant compared with that of nivolumab monotherapy (4.1 vs 2.3 months, P=0.031). Programmed death-ligand 1 (PD-L1) expression positively has no relationship with better PFS in contrast with PD-L1 negatively (3.6 vs 3.0 months P>0.05). Multivariate analysis show nivolumab combined with chemotherapy was only the independent factor for longer PFS (HR: 0.432, P<0.05).ConclusionThe safety of nivolumab in mBTC is controllable. Further selection of superior populations is needed to improve the efficacy of nivolumab in mBTC.

Treatment of MDS, AML and CMML Relapse after Allogeneic Blood Stem Cell Transplantation with Azacitidine, Lenalidomide and Donor Lymphocyte Infusions Results from the Second Interim Analysis of the Prospective Azalena-Trial (NCT02472691)

BackgroundDuring the last years Azacitidine (Aza) in combination with donor lymphocyte infusions (DLI), has proven to be a valuable treatment option for pts with relapse of MDS or AML after allo-SCT. Reasoning that Lenalidomide (Len) may further improve response rate and outcome due to its immunomodulatory and antileukemic properties, we initiated a prospective, multicenter, single-arm phase-II trial evaluating the combination of Aza, Len and DLI in patients with MDS, AML or CMML who had relapsed after allo-SCT. To acknowledge the risk of triggering GvHD with Len this study comprises two safety interim analyses. Results from the interim analysis I on the first 10 pts did not reveal a dose limiting toxicity (DLT) enabling an increase in the daily Len dosage from 2.5 mg to 5 mg in next cohort.Design/Methods:This planned second interim safety analysis (data lock March 2018) was performed in the next 10 pts who were treated with a daily dose of 5 mg Len for 21 days of a 28-day cycle in combination with up to 8 cycles Aza (75 mg/m2/d d1-7, every 28 days) and 3 DLI with increasing T cell dosages (0.5×106 - 1.5×107 cells/kg). In addition, we here present efficacy and safety results of all 24 pts included in this trial so far. The protocol demands a dose reduction of Len to 2.5 mg/day for the remaining 30 patients in case of DLT defined as steroid refractory aGvHD grade III/IV, cGvHD NHI score severe or any unexpected hematologic and non-hematological toxicity grade ≥III in more than 3 pts. In the absence of DLT in more than 3 pts the study will be continued with 5 mg/day.Results:Overall, 24 pts, who had suffered from molecular (54%) or hematological (46%) relapse of MDS (58%), AML (38%) or CMML (4%) after median of 260 days (range, 61-2659) following allo-SCT, were treated with a median of 5.5 cycles of Len per patient (range, 1 to 8; total no. of cycles 121; 83 cycles 2.5 mg/day, 38 cycles 5 mg/day). Concomitantly, pts received a median of 7 courses Aza (range 2-8) and 17 pts (71%) received at least one DLI (median: 2, range: 1-12).No DLT was seen in the cohort of 10 pts treated with a Len dosage of 5mg/day. Furthermore, the increased Len dose did neither result in a higher frequency of dose reductions and treatment interruptions in this cohort, nor to a higher number of AE per cycle (2.5 mg/day: 5.45 AE vs. 5 mg/day: 3.15 AE).We observed an overall response rate of 68% (CR 58%, PR 10%). CR rate was by trend higher in pts with molecular than in those with hematological relapse (67% vs. 43%) and all pts with CR remained in remission for a median of 183 days (range, 113-513) so far. Four pts (17%) developed acute GvHD (overall grade II, II, III, III) and 5 pts (21%) chronic GvHD (mild n=2; moderate n=2; severe n=1). While therapy-related CTC grade III/IV neutropenia (90%), thrombopenia (71%) or anemia (29%) occurred frequently, non-hematological adverse events (AE) >grade II were rare and mainly consisted of gastrointestinal toxicity, laboratory findings and infections.Conclusion:This 2nd interim-analysis of the AZALena-trial shows, that an increase in the Len dosage to 5 mg/day is feasible, safe and not associated with excess GvHD and toxicity. Consequently, 5 mg/day Len will be used in the remaining pts who will be included in this trial (total no. of pts planned, n=50). Furthermore, results from all 24 pts suggest that the combination of Aza, Len and DLI has promising clinical activity and can induce durable responses in a substantial proportion of pts with MDS and AML who relapse after allo-SCT. DisclosuresSchroeder:Celgene: Consultancy, Honoraria, Research Funding. Rautenberg:Celgene: Honoraria. Stelljes:MSD: Consultancy; Pfizer: Consultancy, Honoraria, Research Funding; JAZZ: Honoraria; Amgen: Honoraria; Novartis: Honoraria. Scheid:Celgene: Honoraria; Janssen: Honoraria; Novartis: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; BMS: Honoraria; Amgen: Honoraria. Beelen:Medac: Consultancy, Other: Travel Support. Germing:Janssen: Honoraria; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Kobbe:Celgene: Honoraria, Other: Travel Support, Research Funding; Amgen: Honoraria, Research Funding; Roche: Honoraria, Research Funding.

Final Results of a Phase I Prospective Trial Evaluating the Combination of Stereotactic Body Radiation Therapy (SBRT) with Concurrent Pembrolizumab in Patients with Metastatic Non-Small Cell Lung Cancer (NSCLC) or Melanoma

Synergy between immune checkpoint inhibition and radiation therapy enhances antitumoral immunity in preclinical models. We report the final results of the Phase I portion of a Phase I/II prospective trial designed to assess the safety and tolerability of SBRT delivered with concurrent pembrolizumab. Eligible patients had metastatic NSCLC or melanoma and ≥2 measurable sites of disease. Patients who had received prior anti-PD1 immunotherapy were eligible if their disease had progressed by RECIST criteria; these patients received SBRT at enrollment. Immunotherapy-naïve patients were treated with 200 mg of pembrolizumab q3 weeks until disease progression, then received SBRT. After SBRT, patients received pembrolizumab q3 weeks until coming off study for disease progression. Patients were assigned to an SBRT dose-escalation arm based on target location: either in the lung (arm A) or elsewhere (arm B). Twenty-four patients enrolled in the Phase I portion of the study (melanoma n=5; NSCLC n=19). 9 patients had received prior anti-PD-1 therapy and therefore got SBRT at enrollment. Fifteen patients were immunotherapy-naïve and received a mean of 8.3 cycles of pembrolizumab before disease progression and SBRT. The target SBRT dose of 30 Gy in 3 fractions was reached for each arm. No dose-limiting toxicities (DLTs) were observed within 60 days post-SBRT. Non-hematologic toxicities of grade 2 or higher occurring during the 60-day DLT window or during subsequent pembrolizumab treatment are presented in the table below, with immune-related adverse events noted. 5 of 24 patients (21%) had an immune mediated grade 2 or 3 adverse event during post-SBRT immunotherapy. Patients continued to receive pembrolizumab for a mean of 19.8 weeks post-SBRT (range: 0-52 weeks) before disease progression. We completed escalation to the planned dose of 30 Gy in 3 fractions for both arms without observing dose-limiting toxicity. Combination therapy was well tolerated. Preliminary efficacy data indicates that the addition of SBRT to a single site of disease resulted in a mean of 19.8 weeks of continued response. The phase II portion of the study continues enrollment; progress to date regarding efficacy as well as correlative studies of T cell responses in the peripheral blood will be presented.Abstract 34; TablePre SBRTArm A (Lung Target)Arm B (Non-Lung Target)30 Gy in 5 fx30 Gy in 3 fx30 Gy in 5 fx30 Gy in 3 fxn157647Gr 24 hypothyroid; n=1pneumonitis; n=122 colitis; n=103 pneumonitis; n=1Gr 31 hypothyroid; n=11 pneumonitis; n=12 enterocolitis; n=1pneumonitis; n=101 colitis; n=1Gr 400000Gr 500000 Open table in a new tab

Impact of Body Mass Index (BMI) on Chemotherapy-associated Toxicity in Ovarian Cancer Patients. A Pooled Analysis of the North-Eastern German Society of Gynecological Oncology (NOGGO) Databank on 1,213 Patients.

Chemotherapy-associated toxicity is one of the limiting factors regarding treatment efficacy, patient outcome and quality of life in this collective. Underweight or obese patients represent a major group in which the therapy seems to be more challenging. The aim of this analysis was to evaluate the impact of BMI on the toxicity in patients undergoing chemotherapy. The data of three prospective phase II/III studies ('Tower', 'Topotecan phase III' and 'Hector') of the North-Eastern German Society of Gynecological Oncology including 1,213 patients with recurrent ovarian cancer were retrospectively analyzed. The study was performed using logistic regression and Cox regression analysis. The median age at diagnosis was 59 years. Sixty-seven (5.5%) patients had BMI <20 and 272 (22.4%) patients had BMI >30. Preterm termination of the chemotherapy was associated with lower BMI (p=0.017). Moreover, non-hematological toxicity grade III/IV was mainly observed in underweighted women as well (p<0.001). Patients with higher BMI more often presented with grade III/IV anemia (p=0.019) and as a consequence required blood transfusions more frequently (p=0.005). The overweight group was also associated with a higher number of co-medications. However, no difference in survival regarding BMI was observed in our study. Fewer chemotherapy cycles and preterm discontinuation were more frequent in patients with lower BMI. Hematological toxicity and higher medication intake appeared more often in patients with higher BMI.

Phase 2 Study of an Intravenous Busulfan and Melphalan Conditioning Regimen for Autologous Stem Cell Transplantation in Patients with Multiple Myeloma (KMM150)

This prospective study evaluated the efficacy and toxicity of intravenous busulfan and melphalan as a conditioning regimen for autologous stem cell transplantation (ASCT) in patients with multiple myeloma (MM). A total of 99 patients with MM, enrolled between January 2013 and March 2016, received intravenous busulfan (9.6 mg/kg) and melphalan (140 mg/m2) before ASCT. The median time to transplant was 6.2 months, and 90 (90.9%) patients underwent ASCT within 12 months of the diagnosis. The overall response rate after ASCT was 94.0%, including 43.5% with a stringent complete response/complete response, 27.3% with very good partial response, and 23.2% with partial response. The most common severe nonhematologic toxicity (grade 3 to 4) was infection (26.3%) and stomatitis (15.2%). Three (3.2%) patients developed veno-occlusive disease. No treatment-related mortality was observed. After a median follow-up of 26.1 months, the median progression-free survival was 27.2 months (range, 13.0 to 41.4 months) and median overall survival was not reached. In conclusion, a conditioning regimen of intravenous busulfan and melphalan was effective and tolerable.ClinicalTrials.gov. number: NCT01923935