True Complete Response Research Articles

CTNI-16. MONOGERM, A NOVEL PROOF-OF-PRINCIPLE BAYESIAN PHASE II TRIAL DESIGN OF CARBOPLATIN OR VINBLASTINE MONOTHERAPY INDUCTION PRIOR TO RADIOTHERAPY FOR INTRACRANIAL GERMINOMA

Abstract BACKGROUND Current European standard-of-care for localised intracranial germinoma is multi-agent chemotherapy (carboPEI: carboplatin/etoposide/ifosfamide) followed by definitive radiotherapy, with excellent survival. MonoGerm is a de-escalation, non-inferiority trial aiming to reduce toxicity. Twelve-week carboplatin (PMID:8039122) AUC10 or vinblastine (PMIDs:32642701/34520101) induction will be evaluated to test if as effective as carboPEI from SIOP-CNS-GCT-II. A novel trial design was required to answer this question pragmatically/safely. METHODS Clinical trials in rare diseases recruit slowly, allowing continuous monitoring of efficacy outcomes. Efficacy-transition-pathways (ETP) are innovative visual tools to aid determination of trial design parameters, and an extension of the dose-transition-pathways concept introduced for dose-finding trials (PMID:28733440). RESULTS MonoGerm includes two monotherapies, with each single arm recruiting six cohorts of three patients, with interim assessment after each recruited cohort and final analysis at 18 patients (total n=36). Insufficient tumour volume response (<30%) at 6-week safety MRI results in 12-weeks carboPEI. Primary outcome is radiological complete response (CR) by 12-weeks of induction monotherapy. A beta-binomial conjugate analysis will generate posterior probability distributions, combining observed trial data as realisations from a binomial distribution with a minimally informative Beta (1,1) prior. Decision criteria to allow early stopping at interim analyses and go/no-go decisions at final analysis are based on probabilities from these posterior distributions. ETP visually maps out parameters used to assert decisions after each interim assessment as a pyramid decision tree. For each recruited cohort and every CR outcome, estimates of the true CR rate and probabilities with associated decisions are mapped out. ETP allows clear communication between statisticians, clinicians, and patient-public-involvement (PPI) teams, facilitating informed decisions in an efficient/realistic trial design. CONCLUSION MonoGerm, a novel Bayesian de-escalation trial, funded by Little Princess Trust (https://www.littleprincesses.org.uk/), uses ETP and continuous monitoring with built-in stopping rules to ensure patient safety in this treatment de-escalation trial.

GCT-03. MONOGERM, A NOVEL PROOF-OF-PRINCIPLE BAYESIAN PHASE II TRIAL DESIGN OF CARBOPLATIN OR VINBLASTINE MONOTHERAPY INDUCTION PRIOR TO RADIOTHERAPY FOR INTRACRANIAL GERMINOMA

Abstract BACKGROUND Current European standard-of-care for localised intracranial germinoma is multi-agent chemotherapy (carboPEI: carboplatin/etoposide/ifosfamide) followed by definitive radiotherapy, with excellent survival. MonoGerm is a de-escalation, non-inferiority trial aiming to reduce toxicity. Twelve-week carboplatin (PMID:8039122) AUC10 or vinblastine (PMIDs:32642701/34520101) induction will be evaluated to test if as effective as carboPEI from SIOP-CNS-GCT-II. A novel trial design was required to answer this question pragmatically/safely. METHODS Clinical trials in rare diseases recruit slowly, allowing continuous monitoring of efficacy outcomes. Efficacy-transition-pathways (ETP) are innovative visual tools to aid determination of trial design parameters, and an extension of the dose-transition-pathways concept introduced for dose-finding trials (PMID:28733440). RESULTS MonoGerm includes two monotherapies, with each single arm recruiting six cohorts of three patients, with interim assessment after each recruited cohort and final analysis at 18 patients (total n=36). Insufficient tumour volume response (<30%) at 6-week safety MRI results in 12-weeks carboPEI. Primary outcome is radiological complete response (CR) by 12-weeks of induction monotherapy. A beta-binomial conjugate analysis will generate posterior probability distributions, combining observed trial data as realisations from a binomial distribution with a minimally informative Beta (1,1) prior. Decision criteria to allow early stopping at interim analyses and go/no-go decisions at final analysis are based on probabilities from these posterior distributions. ETP visually maps out parameters used to assert decisions after each interim assessment as a pyramid decision tree. For each recruited cohort and every CR outcome, estimates of the true CR rate and probabilities with associated decisions are mapped out. ETP allows clear communication between statisticians, clinicians, and patient-public-involvement (PPI) teams, facilitating informed decisions in an efficient/realistic trial design. CONCLUSION MonoGerm, a novel Bayesian de-escalation trial, funded by Little Princess Trust (https://www.littleprincesses.org.uk/), uses ETP and continuous monitoring with built-in stopping rules to ensure patient safety in this treatment de-escalation trial.

Sequential T-Cell Engagement for Myeloma (“STEM”) Trial: A Phase 2 Study of Cevostamab Consolidation Following BCMA CAR T Cell Therapy

Background and significance: The BCMA-targeted CAR T products idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel) are currently approved for relapsed/refractory multiple myeloma (RRMM) patients with ≥4 prior lines of therapy, including an IMID, proteasome inhibitor, and CD38 antibody. However, despite unprecedented response rates, CAR T cells are not curative in these late-line patients, even for those in complete remission. Mechanisms of resistance may include lack of persistence or poor function of persisting CAR T cells, as well as BCMA-low or -negative residual tumor cells that serve as a reservoir for relapse. FcRH5 is another MM cell surface antigen, with expression independent of BCMA. Cevostamab is an FcRH5-targeted, T cell-engaging bispecific antibody (bsAb) with demonstrated activity in RRMM, including in patients with prior BCMA-directed therapies (Trudel et al, ASH 2021, #157). We hypothesize that consolidating BCMA CAR T cell therapy with a bsAb targeting a different antigen may re-invigorate persisting CAR+ T cells against residual BCMA+ tumor cells, while also activating endogenous T cells against FcRH5+, BCMA-low/negative tumor cells, ultimately improving rates of sustained minimal residual disease (MRD)-negativity and durability of response. Study design and methods: This is a single-institution, investigator-initiated study (NCT05801939) sponsored by the University of Pennsylvania, with funding support from Genentech. Targeted population are patients with RRMM who have received a commercially available CAR T cell product (ide-cel or cilta-cel) according to the FDA label, within the past 8 weeks, with stable disease or better. Major inclusion criteria include absolute neutrophil count ≥ 1, hemoglobin ≥ 7, platelets ≥ 50, and creatinine clearance ≥ 30 ml/min. Major exclusion criteria include prior cytokine release syndrome or ICANS ≥ grade 3, or any grade hemophagocytic lymphohistiocytosis (HLH) or Parkinsonism, or any active infection. The study schema is shown in Figure 1. Cevostamab is initiated 8-10 weeks after CAR T cell infusion. This timepoint was chosen to allow recovery from acute CAR T cell-related toxicities, but while CAR T cells may still be detectable in circulation. Cevostamab is given at a step-up dose of 3.6mg intravenously (IV) on Cycle 1, Day 1 (C1D1), followed by full dose of 160mg IV on C1D8. Subjects are hospitalized for 48 hours after each C1 dose to monitor for CRS and ICANS. They then continue cevostamab every 3 weeks for total of 8 cycles. If they are in an MRD-negative complete response (CR) after 8 cycles (Adaptive Clonoseq assay, at 10e-5 sensitivity), they stop therapy and are observed. If not, or if bone marrow results are indeterminate, they get another 8 cycles of cevostamab, then stop and are observed. The primary endpoint is frequency of MRD-negative CR at 12 months post-CAR T cell therapy. Assuming a roughly equal proportion of patients enrolling after ide-cel and cilta-cel, the null hypothesis is that the true MRD-negative CR rate at 12 months is 35%. Twenty-six evaluable subjects will be accrued in a single-stage design. The null hypothesis will be rejected if 14 or more subjects meet the primary endpoint. This design yields a one-sided type I error rate of 0.05 and power of 0.84 for an exact test when the true 12-month MRD-negative CR rate is 60%. Secondary endpoints include feasibility, safety/tolerability, and other efficacy measures (overall and CR rates, PFS, OS). Exploratory endpoints include 1) impact of cevostamab on pre- and post-therapy frequency and phenotype of both CAR+ and CAR-negative T cells in blood and marrow, assessed by multiparameter flow cytometry; 2) pre- and post-therapy expression of BCMA and FcRH5 on myeloma cells (when available), serum concentrations of soluble BCMA and FcRH5, and relationship of these factors to clinical outcome measures, and 3) pre- and post-therapy genotypic and phenotypic make-up of bone marrow microenvironment, assessed by single cell RNA sequencing (scRNAseq) and multiparameter flow cytometry, and relationship of these factors to clinical outcome measures. Conclusions: This phase 2 study is exploring the efficacy, safety, and feasibility of cevostamab consolidation following BCMA-directed CAR T cell therapy for RRMM, with the goal of sequential T cell engagement against 2 different antigens to eliminate residual disease. Accrual started in July 2023.

Abstract CT106: Primary tumor response in T1aN0M0 renal cell carcinoma patients ineligible for surgery and treated with nivolumab and ipilimumab: Results from phase 2 pilot study

Abstract Background: Some patients with primary renal cell carcinoma (RCC) are unable to have surgery for different reasons (functional single kidney with a central, high-complexity RCC, high risk of nephrectomy and dialysis, patients with complex coagulation disorders, etc.). We hypothesize that combination of nivolumab and ipilimumab could eliminate the primary tumor in T1aN0M0 patients ineligible for surgical treatment. Methods: This is a prospective, multicenter, non-randomized phase 2 pilot study. Patients with biopsy-proven clear-cell RCC of ≤4 cm (cT1a), no evidence of any metastases, and unable to have surgery or other nephron-sparing interventions (ablation) or with preference to have no surgery or intervention for any reason received combination of ipilimumab (1 mg/kg intravenously) every 3 weeks for four doses, and nivolumab (240 mg intravenously) every 2 weeks during 16 weeks. The primary endpoint was complete response rate. Simon's two-stage design was used. The null hypothesis that the true complete response rate was 11% and was tested against a one-sided alternative. This design yields a type I error rate of 0.05 and power of 0.9 when the true complete response rate is 60% (alternative hypothesis). The null hypothesis should be rejected if 3 or more responses are observed in 8 patients. Results: Between February 2020 and June 2021, 8 patients were included. Median age was 77.9 years (range 73-89). Patients were Caucasian (100%), predominantly male (75%), 62.5% had centrally located RCC, 25% had ECOG PS 1, and 6 of 8 patients had moderate and severe comorbidities. Median follow-up was 12.7 months (95% CI 5.2-16.5). All patients received immunotherapy during 4 months without grade ≥2 adverse events. No complete responses were observed. Partial responses were found in 2 patients (25%). Median size of the primary tumor at RCC diagnosis and after immunotherapy was 3.11 cm (range 2.2-3.9) and 2.86 cm (range 1.5-4.0), respectively. Any shrinkage of the primary tumor was reported in 4 (50%) patients (change in median sum of diameters -18%). Only one patient had tumor enlargement (+0.5 cm (+13%) after 9 months. SBRT was used in this patient. All other patients are under active surveillance. Next secondary end-point of 3-year progression-free survival will be reported. Conclusions: The activity of immunotherapy against primary tumor was limited in patients with T1aN0M0 RCC ineligible for surgical treatment. Duration of stable disease will be studied with long-term follow-up of these patients. Treatment with nivolumab and ipilimumab was safe in patients with moderate and severe comorbidities. Citation Format: Ilya Tsimafeyeu, Maria Volkova, Rustem Gafanov, Igor Myslevtsev, Andrey Andrianov, Axel Bex. Primary tumor response in T1aN0M0 renal cell carcinoma patients ineligible for surgery and treated with nivolumab and ipilimumab: Results from phase 2 pilot study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT106.

Clinical research progress on disappearing colorectal liver metastases

Colorectal cancer is currently one of the most common digestive system tumors, and the liver is the most common metastatic site of colorectal cancer. In recent years, with the continuous development of the multidisciplinary treatment for colorectal cancer patients, there are quite a few cases of disappearing liver metastases (DLM) after receiving preoperative chemotherapy (or combined targeted drug therapy), and the diagnosis and treatment of DLM is currently still a very challenging and controversial topic. This article sorts out the related researches on DLM in recent years, mainly including the following 4 aspects: (1) The factors associated with DLM, including the size and number of liver metastases, chemotherapy regimens and cycles, targeted therapy drugs, and the pattern of liver metastases, Ras/Braf status and the location of the primary lesion. (2) The relationship between DLM and true complete response (pathological complete response and persistent clinical complete response), and the related predictive factors of pathological complete response. (3) Clinical evaluation of DLM: preoperative evaluation includes ultrasound, CT, MRI, and PET, while intraoperative evaluation includes intraoperative exploration, intraoperative ultrasound, and augmented reality. (4) DLM treatment strategies, including surgical treatment, local treatment, non-surgical treatment and individualized treatment.

When is a Ghost Really Gone? A Systematic Review and Meta-analysis of the Accuracy of Imaging Modalities to Predict Complete Pathological Response of Colorectal Cancer Liver Metastases After Chemotherapy.

Administration of chemotherapy to patients with colorectal liver metastases may result in disappearing liver metastases (DLM). This poses a therapeutic dilemma due to the uncertainty of true complete (pathological) response. We aimed to examine the diagnostic performance of imaging modalities in detecting true complete response in patients with DLM after chemotherapy. We performed a systematic search for articles assessing the diagnostic performance of imaging modalities in evaluating DLM following chemotherapy. True complete response was defined as 1-year recurrence-free survival in non-resected patients or complete pathological response on histologic examination in resected patients. We calculated the negative predictive value (NPV) for detecting true complete response of each imaging modality using a random effects model. Thirteen studies comprising 332 patients with at least one DLM were included. The number of DLMs after chemotherapy was 955 withcomputed tomography (CT), 104 withpositron emission tomography (PET), 50with intraoperative ultrasound (IOUS), 585with magnetic resonance imaging (MRI), and 175 withcontrast-enhanced IOUS (CEIOUS). Substantial variation in study design, patient characteristics, and imaging features was observed. Pooled NPV was 0.79 (95% confidence interval [CI] 0.53-0.96), 0.73 (95% CI 0.58-0.85), 0.54 (95% CI 0.37-0.7), 0.47 (95% CI 0.34-0.61), and 0.22 (95% CI 0.11-0.39) for CEIOUS, MRI, IOUS, CT, and PET, respectively. After chemotherapy, MRI or CEIOUS are the most accurate imaging modalities for assessment of DLM and should be used routinely in this context. Given the high NPV of these two modalities, surgical resection of visible CRLM is warranted if technically possible, even if DLM remain.

Treating MRD Positivity in Multiple Myeloma: An Allogeneic GM-CSF-Based Vaccine in Combination with Lenalidomide Induces Long-Term Remissions in Patients with Low Disease Burden

Introduction: Novel therapies have increased the complete response (CR) rates in multiple myeloma (MM) with corresponding improvement in progression free survival (PFS). However, relapse occurs in a significant number of patients. Emerging evidence strongly correlates minimal residual disease (MRD) negativity with improved clinical outcome. Nonetheless, definitive clinical guidance on the management of MRD-positive MM is currently lacking. Here we present the results of a phase II trial evaluating an allogeneic GM-CSF vaccine in combination with lenalidomide (Len) in patients with MM in near CR (NCT01349569). Methods: To be enrolled, patients required a sustained near CR (defined as no measurable M-spike and positive immunofixation, IFE) for at least four months while on a Len-containing regimen. The vaccine consisted of two allogeneic, commercially available MM cell lines (U266 and H929) coupled to a GM-CSF producing leukemia cell line (K562, GVAX®). Patients received four vaccinations over 6 months in combination with Len maintenance for at least 1 year, although in most patients Len was continued until disease progression. The primary endpoints of this trial were eradication of detectable disease and conversion to CR. The secondary endpoints were safety, time to response and immune monitoring of vaccine- and MM-specific T cell responses. Bone marrow (BM) and peripheral blood (PB) samples were collected at pre-established timepoints and cryopreserved for subsequent analyses. The ImmunoSEQ® assay (AdaptiveBiotechnologies, Seattle, WA) was used to sequence T cell receptors (TCR) and the resulting data was used to analyze TCR repertoire metrics. The ImmunoSEQ® assay was also used to sequence the IGH and IGK/L B-cell receptors for MRD quatification. Deep phenotyping of T cells and immune monitoring were performed by flow cytometry. Results: Fifteen MM patients were enrolled. The primary enpoint of the trial was met as 53% (n = 8/15) of patients converted to a true CR (negative IFE) at a median time of 11.6 months (p = 0.011 when compared to the 25% threshold for futility). With a median follow-up of 5.13 years from enrollment, the median PFS could not be estimated as only 6 patients (40%) experienced disease relapse. At the time of the analysis, the median OS was 7.8 years from enrollment (95% CI: 4.2-7.8 years, n = 6/15, 40%). MRD testing was performed on 7 patients. The disease burden threshold of 105/106 cells was arbitrarily used to evaluate the clinical significance of high-level and low-level MRD positivity. Interestingly, all 3 patients with high-level MRD experienced relapse within 1 year of vaccination (median = 4.8 months, range: 2.8 - 9.5 months), while median PFS for low-level MRD patients was significantly prolonged (median = 84.15 months, range: 51.9 - 97.3 months, p = 0.01). Consistently, high-level MRD was associated with increased likelihood of clinical relapse (hazard ratio, HR = 25.79, 95% CI: 2.17 - 306.4). Immune phenotyping of BM CD8+ T cells identified a CD27- DNAM1-/low subpopulation whose abundance was associated with prolonged MM remission. This subset included senescent, effector and exhausted CD8+ T cells and was nearly absent in patients with high-level MRD. Analysis of T-cell repertoires identified vaccine-specific T-cell clonotypes that expanded in both BM and PB of all patients and persisted for up to seven years. Accordingly, polyfunctional T cell responses against vaccine-specific and MM-related antigens were increased and persisted 7 years after enrollment. Despite the correlation between MRD negativity and improved clinical outcome, 47% of patients subsequently developed a detectable M-spike that did not meet criteria for disease relapse nor required any change in treatment. We identified a bone marrow-resident T cell population likely responsible for the establishment of an immune equilibrium mediating long-term disease control. Conclusions: Collectively, these data demonstrate that an allogeneic MM vaccine in combination with Len effectively stimulates antitumor immunity and supports long-term remissions. Although MRD negativity is a critical factor in maintaining remission, the establishment of a MM-MGUS immune equilibrium is likely crucial in the setting of MRD+ MM to prevent disease progression. To our knowledge, this is the first study attempting to treat MRD+ MM in an effort to further improve disease response as well as prevent relapse. Disclosures Sanders: Adaptive Biotechnologies: Current equity holder in private company. Ali:Celgene: Membership on an entity's Board of Directors or advisory committees. Noonan:Aduro: Patents & Royalties. Borrello:WindMIL Therapeutics: Other: Founder , Research Funding; Aduro: Patents & Royalties; Celgene: Research Funding.

A phase II pilot study of the efficacy and safety of nivolumab and ipilimumab in T1aN0M0 renal cell carcinoma patients ineligible for surgical treatment.

TPS769 Background: Surgery remains the standard curative-intent therapy for localized renal cell carcinoma (RCC). Thus, systemic therapy for RCC should only be considered in patients who have contraindications to surgery. The phase 3 CheckMate 214 trial showed that a combination of nivolumab and ipilimumab has a significant impact on tumor burden in intermediate- and poor-risk metastatic RCC patients with a complete response rate of 11%. Median time to objective response was 2.8 months. Among all complete responders to nivolumab plus ipilimumab in the intention-to-treat population, 5% achieved a complete response at the first scan. We hypothesize that this combination could eliminate the primary tumor in T1aN0M0 patients ineligible for surgical treatment. Methods: This is a prospective, multicenter, non-randomized phase 2 pilot study. Patients with biopsy-proven clear-cell RCC of ≤4 cm (cT1a), no evidence of any metastases, and unable to have surgery or other nephron-sparing interventions (ablation) for any reason (functional single kidney with a central, high-complexity RCC, high risk of nephrectomy and dialysis, patients with complex coagulation disorders, etc.) or with preference to have no surgery or intervention for any reason will receive combination of ipilimumab (1 mg/kg intravenously) every 3 weeks for four doses, and nivolumab (240 mg intravenously) every 2 weeks during 16 weeks. The primary endpoint is complete response rate. Simon's two-stage design (Simon, 1989) is used. The null hypothesis that the true complete response rate is 11% will be tested against a one-sided alternative. This design yields a type I error rate of 0.05 and power of 0.9 when the true complete response rate is 60% (alternative hypothesis). In the first stage, 3 patients will be accrued. If there are no complete responses in these 3 patients, the study will be stopped. Otherwise, 5 additional patients will be accrued for a total of 8. The null hypothesis will be rejected if 3 or more responses are observed in 8 patients. Clinical trial information: NCT04134182.

ZUMA-11: A Phase 1/2 Multicenter Study of Axicabtagene Ciloleucel (Axi-Cel) + Utomilumab Patients with Refractory Large B Cell Lymphoma

Background: Relapsed/refractory (R/R) large B cell lymphoma (LBCL) is associated with poor outcomes to standard salvage therapy (Crump M, et al. Blood. 2017). In SCHOLAR-1, a large multicenter, patient-level, retrospective study, patients with R/R diffuse LBCL had a 26% objective response rate (ORR) to the next line of therapy, a 7% complete response (CR) rate, and a median overall survival of 6.3 months (Crump M, et al. Blood 2017). Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy approved for patients with R/R LBCL with ≥ 2 prior systemic therapies. With a median follow-up of 27.1 months in ZUMA-1, the ORR with axi-cel was 83% (58% CR rate) in patients with refractory LBCL (Locke FL, et al. Lancet Oncol. 2019). Activation of the costimulatory receptor 4-1BB (CD137) on CAR T cells may enhance axi-cel antitumor activity by enhancing T cell proliferation, function, and survival. Utomilumab (uto), an investigational monoclonal antibody agonist of the 4-1BB pathway, enhanced T cell function and survival in preclinical studies (Fisher TS, et al. Cancer Immunol Immunother. 2012) and had favorable single-agent safety in patients (Segal NH, et al. Clin Cancer Res. 2018). Possible mechanisms of resistance to axi-cel are thought to be suboptimal CAR T cell expansion an exclusionary tumor microenvironment and CD19 target antigen loss (Neelapu SS, et al. Blood 2017, Rossi JM, et al J Immunother Cancer. 2018). Combination strategies that increase proliferation, expansion, and persistence of CAR T cells or prevent activation-induced cell death of CAR T cells may improve clinical outcomes observed with axi-cel. ZUMA-11 is a Phase 1/2 study investigating the efficacy and safety of axi-cel + uto in patients with refractory LBCL. Methods: The primary objectives of this study are to determine the safety, recommended Phase 2 dosing and timing (Phase 1), and efficacy (Phase 2) of axi-cel + uto in adult patients with refractory LBCL. Patients with progressive or stable disease as the best response to second-line chemotherapy or relapse ≤ 12 months after autologous stem cell transplantation, a prior anti-CD20 antibody and anthracycline-containing regimen, and Eastern Cooperative Oncology Group performance status 0-1 are eligible. Patients with histologically proven primary mediastinal B cell lymphoma, history of Richter's transformation or chronic lymphocytic lymphoma, prior CAR T cell therapy, or central nervous system involvement of lymphoma are ineligible. In Phase 1, ≈24 patients in ≤ 3 cohorts will receive a single dose of axi-cel and escalating doses of uto (10, 30, or 100 mg) using a 3 + 3 design in up to 4 of 6 cohorts. The recommended uto dose will be based on dose-limiting toxicities and other factors. Patients will be leukapheresed and may receive optional, nonchemotherapy bridging therapy per investigator decision. After conditioning chemotherapy, patients will receive a single infusion of axi-cel (target dose, 2 × 106 CAR T cells/kg) on Day 0 followed by uto on Day 1 and every 4 weeks for 6 months or until progressive disease. Patients will be treated one at a time during Phase 1, and patients treated with axi-cel will be staggered by ≥ 2 weeks. Day 21 uto administration will be explored if toxicity is unacceptable with Day 1 administration. The primary endpoints are incidence of dose-limiting toxicities in Phase 1 and CR rate in Phase 2. Secondary endpoints include ORR, duration of response, progression-free survival, overall survival, safety, and levels of CAR T cells and cytokines in blood. This study uses a single-arm design to estimate the true CR rate; with a sample size of 27 patients, of which ≤ 3 patients will have been treated in the Phase 1 portion, the maximum half-width of the 95% confidence interval about response will be ≥ 21%. ZUMA-11 is open and accruing patients. Disclosures Reshef: Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Celgene: Research Funding; Incyte: Consultancy, Research Funding; Shire: Research Funding; BMS: Consultancy; Atara: Consultancy, Research Funding; Magenta: Consultancy; Pfizer: Consultancy; Pharmacyclics: Consultancy, Research Funding. Miklos:Pharmacyclics: Consultancy, Patents & Royalties, Research Funding; Precision Bioscience: Consultancy; Adaptive Biotechnologies: Consultancy, Research Funding; Miltenyi: Consultancy, Research Funding; Becton Dickinson: Consultancy; Janssen: Consultancy; AlloGene: Consultancy; Novartis: Consultancy; Kite, A Gilead Company: Consultancy, Research Funding; Celgene-Juno: Consultancy. Timmerman:Spectrum Pharmaceuticals: Research Funding; Kite, A Gilead Company: Consultancy, Honoraria, Other: travel support, Research Funding; ImmunGene: Research Funding; Merck: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Other: travel support, Research Funding. Jacobson:Novartis: Consultancy, Honoraria, Other: travel support; Bayer: Consultancy, Other: travel support; Precision Biosciences: Consultancy, Other: travel support; Humanigen: Consultancy, Other: travel support; Celgene: Consultancy, Other: travel support; Pfizer: Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Other: travel support. Bennani:Kite, A Gilead Company: Consultancy, Research Funding. Rossi:Kite, A Gilead Company: Employment. Sherman:Kite, A Gilead Company: Employment. Sun:Kite, A Gilead Company: Employment. Palluconi:Kite, A Gilead Company: Employment. Kim:Kite, A Gilead Company: Employment. Jain:Kite/Gilead: Consultancy.

Treatment response in the neck: p16+ versus p16− oropharyngeal cancer

To compare nodal response rates following chemoradiotherapy in patients with p16+ and p16- oropharyngeal squamous cell carcinoma (OPSCC). Patients with node-positive OPSCC treated at Peter MacCallum Cancer Centre on the published phase I-III tirapazamine trials were identified. All patients had conventional assessment (clinical examination (CA), CT and/or MRI) and positron emission tomography (PET) at both baseline and 2-4 months post-treatment. There were 30 p16+ and 18 p16- patients, the former group having significantly higher stage nodal disease (P = 0.016). The mean overall reduction in nodal size at post-treatment assessment was similar in p16+ and p16- patients (78% vs. 75%), and no statistically significant difference in nodal complete response (CR) rates was detected by either CA (50% vs. 39%, P = 0.35) or PET/PET-CT (93% vs. 83%, P = 0.19). PET was significantly more accurate in determining the true nodal CR rate in both groups, with a negative predictive value of 96%. Nodal response rates following chemoradiotherapy appear to be similar in p16+ and p16- patients when assessed by either CA or PET/PET-CT. However, higher nodal CR was seen in PET/PET-CT compared with CA in both groups. Metabolic imaging is more accurate than CA in assessing nodal response post-treatment.

Predictors of a true complete response among disappearing liver metastases from colorectal cancer after chemotherapy

During chemotherapy, some colorectal liver metastases (LMs) disappear on serial imaging. This disappearance may represent a complete response (CR) or a reduction in the sensitivity of imaging during chemotherapy. The objective of the current study was to determine the fate of disappearing LMs (DLMs) and the factors that predict a true CR. Between 2000 and 2003, 435 patients who were evaluated by hepatobiliary surgeons received chemotherapy before they were considered for resection. Inclusion criteria were <12 LMs before chemotherapy, at least 1 DLM on a computed tomography (CT) scan, and either surgical resection or 1 year of clinical follow-up after the disappearance of LMs. A true CR was defined as either a pathologic CR (no tumor detected in the resection specimen) or a durable clinical CR (did not reappear on follow-up imaging). Clinical and pathologic factors were analyzed to identify those associated with a true CR. During chemotherapy, 39 patients (9%) had a total of 118 DLMs on follow-up CT scans. Sixty-eight DLMs were resected, and 50 were followed clinically. Overall, 75 DLMs (64%) were true CRs, including 44 pathologic CRs and 31 durable clinical CRs. On multivariate analysis, the use of hepatic arterial infusion (HAI) chemotherapy (odds ratio [OR], 6.2; P = .02), the inability to observe the DLM on a magnetic resonance image (OR, 4.7; P = .005), and normalization of serum carcinoembryonic antigen levels (OR, 4.6; P = .006) were associated independently with a true CR. Approximately 66% of DLMs represented a true CR according to assessment by resection or radiologic follow-up. Predictive factors may help to stratify patients who are likely to harbor residual disease.

Management of the neck after chemoradiotherapy for head and neck cancers in Asia: consensus statement from the Asian Oncology Summit 2009

The addition of a planned neck dissection after radiotherapy has traditionally been considered standard of care for patients with positive neck-nodal disease. With the acceptance of chemoradiotherapy as the new primary treatment for patients with locally advanced squamous-cell head and neck cancers, and the increasing numbers of patients who achieve a complete response, the role of planned neck dissection is now being questioned. The accuracy and availability of a physical examination or of different imaging modalities to identify true complete responses adds controversy to this issue. This consensus statement will address some of the controversies surrounding the role of neck dissection following chemoradiotherapy for squamous-cell carcinomas of the head and neck, with particular reference to patients in Asia.

Treatment for Patients with Rectal Cancer and a Clinical Complete Response to Neoadjuvant Therapy

A clinical complete response to neoadjuvant therapy occurs in a subset of patients with rectal cancer. Management of these patients is controversial and tension exists between the recurrence risk with observation, and the impact of surgery on quality-of-life. Therefore, the objective was to develop a decision-analytic model to evaluate the relative benefits of surgery vs. observation in rectal cancer patients who achieve clinical complete response after neoadjuvant chemoradiation. Clinically relevant inputs and events, including the ability to identify complete responders, likelihood of relapse and of salvage surgery after relapse, and utilities for each health state, were simulated by use of a Markov state-transition model. Transition probabilities and health-state utilities were derived from the literature and expert consensus. One-way and two-way sensitivity analyses were performed to assess the robustness of model results to assumptions. The primary outcome was quality-adjusted life expectancy. In the base-case analysis, the quality-adjusted life expectancy with surgery exceeded observation (5.63 vs. 5.34 quality-adjusted life-years). Sensitivity analysis demonstrated that observation was preferred to surgery if the ability to correctly identify patients with true complete responses exceeded 58 percent, if quality-of-life after surgery was poor (utility <0.81), or if the relative reduction in recurrence risk with surgery was <43 percent when compared with observation. Our model outlines the issues associated with surgery vs. observation, and suggests that surgery is beneficial for the average patient with rectal cancer with a clinical complete response after neoadjuvant therapy. Current limitations in the clinical assessment of patient response to chemoradiation constitute an important factor influencing our results, and therefore warrant further investigation.

Three years' continuous low-dose interferon-alpha treatment of hairy-cell leukaemia: evaluation of response and maintenance dose.

Thirty-six HCL patients were treated with 2 x 10(6) U/m2 IFN-alpha-2b three times weekly for 24 months, followed by 12 months of treatment with one of three doses ranging from 0.5 x 10(6) U to 2 x 10(6) U/m2. For most patients the response continued to improve during the whole treatment period, and there were no cases of disease progression during treatment. Patients with disease of short duration before IFN treatment and/or non-splenectomized patients seemed to respond more slowly than others, but there were no differences between patients treated with the different IFN doses. Toxicity was usually WHO grade 1 or 2. The continued improvement in a large number of patients even with very small IFN doses might indicate that only a small number of true complete responses are reached after 24 months of treatment, thus explaining the reported high relapse rate after early discontinuation of treatment. It therefore seems worthwhile--also from a cost/benefit point of view--to test long-term or continuous IFN-alpha treatment at other centres.

The Importance of Bone Marrow Examination in Determining Complete Response to Therapy in Patients with Multiple Myeloma.

Background: In multiple myeloma (MM), a complete response (CR) is defined by the European Group for Blood and Bone Marrow Transplantation (EBMT) and the International Myeloma Working Group (IMWG) Uniform Response Criteria as absence of monoclonal protein in serum and urine by immunofixation (IFE), and a bone marrow (BM) aspirate/biopsy containing <5% plasma cells (PC). This definition of CR is widely adopted in clinical trials, but there is a high degree of non-compliance with the BM requirement. As a result, differences in CR rates across trials can occur not just as a result of treatment efficacy, but also on how rigorously the BM requirement for CR is implemented. Moreover, requiring BM examinations merely to confirm CR is cumbersome in clinical practice. The goal of this study was to determine the added value of BM examinations in patients who can otherwise be considered to be in CR by virtue of a negative IFE in the serum and urine.Methods: For the purpose of the study, we included only patients with MM who had measurable monoclonal (M) protein levels at baseline (defined as >1 gm/dL in the serum and/or >200 mg/24 hour in the urine) on protein electrophoresis; patients with non-secretory and oligo-secretory MM were excluded. We then identified patients who since 1995 had a negative IFE in the serum and urine and a BM aspirate/biopsy, all done at the same time (within 30 days of each other). Baseline demographics and clinical characteristics; date of diagnosis, last follow up, and follow up status; serum and urine M protein levels at diagnosis; and results of serum and urine IFE, serum free light chain (FLC) ratio and BM aspirate/biopsy within 30 days of complete response were all collected from the existing databases.Results: Ninety-five patients met the criteria for the study, all of whom had measurable disease at baseline and subsequently achieved negative IFE in serum and urine (‘IF- CR‘). Of these, only 83 patients (87%) met criteria for CR by the EBMT/IMWG criteria with less than 5% PC in the BM; 13% of patients had 5% or more PC despite the apparent IF-CR on serum and urine IFE. In fact, the BM showed 10% or more PC in 5% of IF-CR patients. We then assessed whether a normal serum FLC ratio in addition to negative serum and urine IFE would eliminate the need for a BM biopsy. The additional requirement of the serum FLC ratio to negative IFE was not fully adequate in eliminating false positive CR's. Among 34 patients who had IF- CR plus a normal serum FLC ratio, only 88% of patients met CR definition with <5% BM PC; 12% had 5% or more PC, and one patient (3%) had 10% or more PC. We studied the survival (from time of diagnosis) of patients who had true CR's (negative IFE and <5% PC) versus patients who had IF- CR's but BM had 5% or more PC. Overall survival from diagnosis between the two groups was 10.7 years versus 5.6 years, respectively, P=0.001 (see Figure 1).Conclusions: BM examination is essential to accurately estimate CR. Up to 13% of patients with negative IFE in serum and urine fail to meet the BM requirement. The addition of a normal serum FLC ratio to negative IFE did not significantly reduce the proportion of patients who fail to meet the BM requirement. Based on this study, we recommend that the CR definition in the EBMT and IMWG criteria should not be revised to eliminate the need for BM examination. Moreover, the consistent collection of BM samples is essential for future strategies to evaluate immunophenotypic CR and molecular CR in MM. [Display omitted]

Predictors of a true complete response in colorectal liver metastases that disappear radiographically following chemotherapy

4058 Background: During chemotherapy for colorectal liver metastases (LM), some lesions disappear by CT scan. This may represent a true complete response (CR) with eradication of tumor or a reduced sensitivity of imaging due to chemotherapy induced hepatic steatosis. This study aimed to determine the significance of radiologic disappearance of LM treated with chemotherapy and factors predictive of a true CR. Methods: Between 2000 and 2003, 435 patients evaluated by a hepatobiliary surgeon were treated with neoadjuvant chemotherapy for LM. Inclusion criteria were fewer than 12 LM initially, disappearance of one or more LM by CT scan and a clinical follow-up of at least 1 year after disappearance. A pathologic CR (pCR) was defined as the absence of a LM in the resected specimen, a durable clinical CR (cCR) was defined as a LM that did not reappear during follow-up imaging. A LM was defined as found if it was detected by other imaging (MRI), at resection, or if it recurred during follow-up. LM that were found were compared to pCR and durable cCR to determine factors predictive of a true CR. Results: During chemotherapy, 39 (9%) patients had a total of 117 LM disappear by follow-up CT scan. The outcome is shown in the Table . Treatment with hepatic arterial infusion (HAI) chemotherapy (n=22) was associated with a significantly higher rate of pCR or durable cCR (42% vs. 14%, p&lt;0.001). LM were also significantly more likely to represent a pCR or durable cCR when the surrounding liver did not demonstrate steatosis (p&lt;0.001), when the patient’s BMI was &lt;30 kg/m2 (p=0.002), and when a preoperative MRI was performed (p=0.01). Conclusions: Among disappearing LM, a pCR occurs in 37% and a durable cCR in 26%, yielding a true CR rate of 63%. The disappearing LM in patients treated with HAI chemotherapy were more likely to a represent true CR when compared to systemic chemotherapy alone. Hepatic steatosis and obesity impaired the ability to detect lesions by CT scan and MRI improved the preoperative detection rate of disappearing LM. [Table: see text] No significant financial relationships to disclose.

Rituximab Is an Alternative to Splenectomy in Adults with Chronic Immune Thrombocytopenic Purpura: Results of a Multicenter Prospective Phase 2 Study.

Background : Rituximab, a monoclonal anti-CD20 antibody, is a promising therapeutic agent for adults with immune thrombocytopenic purpura (ITP). Pooling results of the published literature suggest that rituximab achieves an initial response in about 50 % of adults with chronic ITP, with a 25–40% rate of sustained response. However, heterogeneity of patient pre-treatment status, short follow up and bias due to retrospective studies limit the interpretation of the data.Objective : To assess the safety and efficacy of rituximab in adults with chronic ITP (duration ≥ 6 months) and platelet count ≤ 30x109/L candidate to splenectomy.Methods : a multicenter prospective open-label single arm phase 2 trial designed according to Fleming's single stage procedure was conducted. After informed consent, non splenectomized adults received 4 weekly intravenous infusions of rituximab at a dose of 375 mg/m2. All other ITP treatments were stopped. Treatment success was defined as a platelet count ≥ 50 x109/L with at least a 2 fold increase of the initial value at one year after the first rituximab infusion. Patients who received another treatment during follow up were considered as non responders. A sample size of at least 56 patients was calculated by Fleming's single-stage design to ensure 90 % power for proving lack of efficacy if the true complete response rate was below 25%.Results : Sixty consecutive patients (40F/20M) were included over a 21 months period. Mean age was 48 years (range 18–84). Mean ITP duration was 4.8 years. Mean platelet count at inclusion was 16±10x109/L. All but one patient, in whom reversible serum sickness disease was diagnosed after 2 infusions, received 4 infusions of rituximab. Fifteen other patients experienced transient side effects that did not lead to treatment discontinuation. No patient was lost to follow up. Success was achieved in 40 % (24/60 patients) (95 % confidence interval 28% to 52%) and was found significantly different from 25% (p=0.007). Among the 24 long term responders, platelet count at one year was ≥ 150x109/L in 18 and between 50 and 150 x109/L in 6. Two other patients (3%) had and incomplete response defined as a platelet count at one year between 30 and 50 x109/L but at least 2 fold the initial value. Thirty four (57%) patients failed to respond and amongst them, 18 have already undergone splenectomy.Conclusion: rituximab appears to be a safe and good splenectomy-sparing strategy in adults with chronic ITP leading to a significant and durable response in 40% of the cases.

Gallium Scan in the Evaluation of Post Chemotherapy Mediastinal Residual Masses of Aggressive Non-Hodgkin's Lymphoma

Optimal evaluation of residual masses of non Hodgkin's lymphomas (NHL) after chemotherapy is of major importance, and gallium scan (GS) is routinely used for this purpose, particularly for mediastinal sites. However, sensitivity and specificity of GS in this setting has been diversely appreciated and needs to be more accurately defined especially if radiotherapy is not planned. A retrospective analysis selected all the patients treated in a single institution for aggressive NHL who presented a residual mass in the mediastinum after chemotherapy and who were evaluated by GS. The value of GS for distinguishing true complete responses (CR) from partial responses (PR) was analyzed in patients who were either submitted to resection of their residual mass or followed up without further treatment after GS. A residual mass with mean perpendicular diameters measuring 4.1 cm × 2.8 cm was found in 42 patients and was GS positive in 8 cases and negative in 34 cases. After GS, radiotherapy was delivered to 10 patients, but 12 patients underwent resection of their residual mass and 20 were followed up without further treatment. In the patients who did not receive radiotherapy, 3 false positive and 6 false negative GS results were disclosed. The specificity and the sensitivity of GS were 88% and 25%, and its positive predictive value and negative predictive value 40% and 78 %, respectively. GS was not sufficiently reliable to evaluate post chemotherapy residual masses. Surgical resection of residual masses should be considered particularly in young patients. Patients in true CR should be spared pointless radiotherapy and its late side effects, while patients in PR may benefit from further intensified chemotherapy followed by radiotherapy.

Current Status of U.S. Clinical Trials in Chronic Lymphocytic Leukemia.

Current therapies for chronic lymphocytic leukemia (CLL) have not substantially improved the survival of these patients (pts). As a result treatment has been primarily palliative. One major obstacle in designing innovative therapies has been a lack of new and effective agents. Recent interest in clinical trials has been stimulated by the impressive activity in pts with CLL of three unique purine analogues; fludarabine (FLUDARA), 2'-deoxycoformycin (DCF) and 2-chlorodeoxyadenosine (CDA). Of the three, the largest experience in CLL is with FLUDARA. More than 1200 CLL patients have received FLUDARA either on clinical trials or through the NCI-Group C protocol mechanism. In contrast to the published data, preliminary analysis of the first 87 evaluable Group-C patients revealed only 2% complete and 37% partial responses; this discrepancy can be explained by the fact that most patients were still receiving treatment at the time of the analysis, and many were continuing to respond (9 of 12 patients who received treatment for > 6 cycles responded); there was no central pathology review to confirm the diagnosis, 89% were Rai "high risk", and most patients had received extensive prior therapy. An updated analysis of response in the first 300 cases is underway. Of 497 pts evaluable for toxicity, 41% developed infections which were serious in 17%, and there were episodes of serious neurotoxicity in 9%. Based on the high level of activity and relative tolerability of FLUDARA, a national U.S. phase III trial is underway comparing chlorambucil (CLB) vs FLUDARA vs CLB + FLUDARA in untreated patients with advanced disease. A comparison of FLUDARA vs CDA in relapsed/refractory pts is being planned. Combination regimens are being piloted in relapsed/refractory CLL including DCF + FLUDARA, DCF + CLB, FLUDARA + CDA, FLUDARA + interferon-alpha, FLUDARA + gallium, FLUDARA + cyclophosphamide. Since FLUDARA achieves true complete responses in a substantial number of previously untreated pts, it is being considered as part of an induction program prior to autologous bone marrow transplantation. FLUDARA has a high degree of bioavailability in dogs, and an oral preparation is being evaluated in clinical trials. Hopefully, new purine analogue-based combination regimens will improve the response rate and survival in patients with CLL.