A Randomized, Double-Blind, Placebo-Controlled, Phase II Study of MBG453 Added to Hypomethylating Agents (HMAs) in Patients (pts) with Intermediate, High, or Very High Risk Myelodysplastic Syndrome (MDS): Stimulus-MDS1

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4259-4259 ◽  
Author(s):  
Amer M Zeidan ◽  
Yasushi Miyazaki ◽  
Uwe Platzbecker ◽  
Kamel Malek ◽  
Julie Niolat ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Stem Cells ◽  
Bone Marrow ◽  
High Risk ◽  
Research Funding ◽  
Leukemic Stem Cells ◽  
Double Blind ◽  
Free Survival ◽  
Double Blind Placebo ◽  
Very High

Background and Rationale: Pts with higher-risk (HR; intermediate, high, or very high risk) MDS experience poor outcomes and have limited treatment options as most such pts are older and not candidates for the only potentially curative therapy: allogeneic hematopoietic stem cell transplantation (alloHSCT). HMAs are approved for the frontline (1L) management of HR-MDS, but 50% of HMA-treated pts experience primary failure and most responders progress within 1-2 yr. Furthermore, pts often require 4-6 months of HMA therapy before a response is seen, and deep responses (e.g., complete responses or complete cytogenetic responses) are rare. Although azacitidine is the only drug shown to prolong overall survival (OS) in HR-MDS (AZA-001 study; Fenaux et al, 2009), accumulating evidence suggests that the median OS achieved with azacitidine at the population level may be shorter than the 24 months reported in this landmark trial. Thus, there is an urgent need for novel therapies in the 1L setting of HR-MDS. T-cell immunoglobulin domain and mucin domain-3 (TIM-3) is an inhibitory receptor with a key role in regulating not only adaptive but also innate immune responses. TIM-3 is also preferentially expressed on leukemic stem cells and blasts, and expression of TIM-3 correlates with severity of MDS. TIM-3 is therefore a promising therapeutic target whose blockade may restore immune function-or reawaken immunity-while also directly targeting leukemic stem cells. MBG453 is a high-affinity, humanized, anti-TIM-3 IgG4 monoclonal antibody that blocks binding of TIM-3 to its ligand, phosphatidylserine. In an early clinical trial, MBG453 demonstrated a good safety/tolerability profile in pts with advanced solid tumors and an ongoing phase I study is evaluating MBG453 plus decitabine in HR-MDS and acute myeloid leukemia (AML). We present here the study design of an ongoing large, international, multicenter phase II clinical trial (STIMULUS-MDS1; NCT03946670) evaluating MBG453 combined with HMAs in 1L management of pts with HR-MDS. Methods: The primary objective of this randomized, double-blind, placebo-controlled study is to evaluate whether addition of MBG453 to standard HMA improves the complete remission (CR) rate and progression-free survival (PFS) compared with HMA alone in pts with HR-MDS. Secondary objectives include assessment of OS, leukemia-free survival (LFS), transfusion independence, and safety, and characterization of pharmacokinetics and immunogenicity. Eligible pts are aged ≥ 18 yr with a confirmed diagnosis of MDS categorized based on the Revised International Prognostic Scoring System (IPSS-R) as very high risk (> 6 points), high risk (> 4.5-6 points), or intermediate risk (> 3-4.5 points) with ≥ 5% bone marrow blasts at baseline. Pts considered candidates for alloHSCT at the time of screening are not eligible. Additional exclusion criteria include diagnosis of AML or chronic myelomonocytic leukemia, prior treatment with anti-TIM-3 therapy, or prior treatment for HR-MDS with chemotherapy or HMAs. Pts with therapy-related MDS are allowed. Responses will be recorded using modified International Working Group 2006 criteria. PFS will be measured from randomization until progression, relapse from CR, or death. LFS will be measured from randomization until detection of ≥ 20% blasts in bone marrow/peripheral blood, or death. Biomarker assessments will be conducted using pt samples. Approximately 120 pts will be randomized in a 1:1 ratio to receive either MBG453 combined with an HMA or placebo combined with an HMA in 28-d treatment cycles. Selection of the HMA (decitabine or azacitidine) is per investigator's choice based on local standard of care. Randomization will be stratified by the HMA and IPSS-R risk category. MBG453 (400 mg) or placebo will be administered intravenously (IV) on D8 and D22 of each cycle. Decitabine will be administered IV at 20 mg/m2 on D1 to D5 of each cycle; azacitidine will be administered IV or subcutaneously at 75 mg/m2 on D1 to D7 or, alternately, on D1 to D5 plus D8 and D9 of each cycle. All pts who discontinue study treatment will be followed for efficacy (if they have not progressed/relapsed) and survival status until approximately 108 PFS events have been observed or for up to 4 yr after the last pt is randomized. This study is ongoing and will enroll pts in several countries, including the United States. Disclosures Zeidan: Cardinal Health: Consultancy, Honoraria; MedImmune/AstraZeneca: Research Funding; Jazz Pharma: Consultancy, Honoraria; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; BeyondSpring: Consultancy, Honoraria; ADC Therapeutics: Research Funding; Incyte: Consultancy, Honoraria, Research Funding; Celgene Corporation: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Otsuka: Consultancy, Honoraria, Research Funding; Trovagene: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Acceleron Pharma: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Agios: Consultancy, Honoraria; Ariad: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding. Miyazaki:Nippon-Shinyaku: Honoraria; Novartis: Honoraria; Dainippon-Sumitomo: Honoraria; Kyowa-Kirin: Honoraria; Chugai: Research Funding; Otsuka: Honoraria. Platzbecker:Novartis: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding. Malek:Novartis: Employment; Novartis: Equity Ownership. Niolat:Novartis Pharma: Employment. Kiertsman:Novartis Pharmaceuticals Corporation: Employment, Other: Employment includes stock options. Fenaux:Jazz: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding; Astex: Honoraria, Research Funding; Aprea: Research Funding. OffLabel Disclosure: MBG453 is an investigational anti-TIM-3 antibody that is being evaluated in hematological malignancies and solid tumors

scholarly journals Clinical Characteristics and Treatment Allocations in Patients with Myelodysplastic Syndromes and Monosomy 7: Results from an International Multicenter Study Suggest That Hypomethylating Agents Significantly Improve Overall- and AML-Free Survival in Patients Classified As Very High Risk By IPSS-R

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4656-4656 ◽  
Author(s):  
Julie Schanz ◽  
Friederike Braulke ◽  
Ghulam J. Mufti ◽  
Elena Crisà ◽  
Austin Kulasekararaj ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Research Funding ◽  
Risk Group ◽  
Best Supportive Care ◽  
High Risk Group ◽  
Study Cohort ◽  
Monosomy 7 ◽  
Free Survival ◽  
Very High

Abstract Introduction: Total (-7) or partial (7q-) monosomy 7 is the second frequent abnormality in MDS, occurring in around 12% of MDS/AML and up to 40% of therapy-associated MDS/AML. The present study was designed to analyze clinical features, prognosis and response to different therapeutic strategies in patients with -7 or del(7q) in a multicentric, retrospective cohort study. Patients and Methods: 471 patients with MDS/AML following MDS and monosomy 7 were registered and retrospectively analyzed. The median observation time was 3.6 years. Inclusion criteria were defined as follows: Morphologic diagnosis of MDS/AML following MDS, bone marrow blast count <=30% and presence of -7 or 7q- proved by chromosome banding analysis (CBA) or fluorescence in situ-hybridization (FISH). The data was coalesced from 8 centers in London (n=140; 29.7%), Duesseldorf, (n=120; 25.5%%), Goettingen (n=118; 25.1%), Cologne (n=38; 8.1%), Freiburg (n=29; 6.2%), Munich (n=13; 2.8%), Dresden (n=10; 2.1%) and Mannheim (n=3; 0.6%). The median age in the study cohort was 66 years, 63% of patients were males. MDS/AML was therapy-associated in 53 (11%). According to IPSS-R, 9 (1.9%) were assigned to the low risk group, 39 (8.3%) to the intermediate group, 81 (17.2%) to the high-risk group and 133 (28.2%) to the very high risk group. The treatment was classified as follows: Best supportive care (BSC), low-dose Chemotherapy (LDC), high-dose chemotherapy (HDC), hypomethylating agents (HMA; either 5-azacytidine or decitabine), and others (e.g. valproic acid, steroids, lenalidomide or thalidomide). Survival analyses were performed regarding overall- (OS) as well as AML-free survival (AFS) using the Kaplan-Meier method. Results: 147 patients (31.2%) showed 7q-, 313 (66.5%) -7 and 11 (2.3) patients showed both abnormalities at the first cytogenetic examination. The abnormality was detected by CBA±FISH in 440 (93.4%) and by FISH only in 31 (6.6%). In the latter cases, the CBA was either unsuccessful or showed a normal karyotype. In 182 (38.6%) patients, -7/del7q was detected as a single abnormality, 77 (16.3%) showed two abnormalities and 184 (39.1%) showed a complex karyotype involving -7/7q-. As previously described (Schanz et al., 2012), untreated patients with an isolated 7q- as compared to an isolated -7 show a better prognosis regarding OS (median: 4.0 vs. 0.7 years; p<0.01) as well as AFS (median not reached vs. 2.3 years; p=0.062). Median hemoglobin level in the study cohort was 9.3 g/dl, ANC 0.98*103/μl, platelet count 73*103/μl and the median number of bone marrow blasts was 8%. Regarding the treatment, a best supportive care regimen was chosen in 195 (41%) patients. The remaining 276 (58.6) patients received 1-5 sequential therapies (one therapy: 31.6%; more than 1 therapy: 27.0%). 81 patients received an allogeneic bone marrow transplantation (ATX). Within the group of patients treated with HMA at any time of their disease (n=167), 147 (31.2%) received 5-Azacytidine, 8 (1.7%) Decitabine and 12 (2.5%) patients were treated with both drugs. As the first line therapy, 122 patients (25.9%) received HMA, 50 (10.6%) HDC, 28 (5.9%) ATX, 28 (5.9%) 11 (2.3%) LDC, and 28 (5.9%) were treated with other therapies. Patients eligible for ATX showed a significantly better prognosis as compared to any other therapy strategy: The median OS in was 2.1 years as compared to 1.1 years in non-transplanted patients (p<0.01). In patients not eligible for ATX, treatment with HMA at any course of their disease as compared to a BSC strategy was associated with a better OS (1.4 vs. 0.8 years, p=0.014). By comparing HMA to any other therapy, the OS did not differ significantly (1.4 years in HMA vs. 1.1 years in any other, p n.s.). In patients classified as very high risk according to IPSS-R, the median OS was significantly prolonged in patients receiving HMA as compared to BSC (1.1 vs. 0.6 years, p<0.01). This was also observed for the risk of AML-transformation in this subgroup of patients: The median time to AML was 1.8 years in HMA-treated patients versus 0.6 years in BSC (p=0.012). Conclusions: To our knowledge, the study describes the largest patient cohort with MDS/AML and monosomy 7 published to date. Further data regarding the clinical characteristics of this subgroup of patients and the treatment regimes applied will be presented in detail. The study was supported by research funding from Celgene Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Schanz: Celgene: Honoraria, Research Funding, Travel grants: Celgene, Novartis, Lilly Other. Götze:Celgene Corp, Novartis Pharma: Honoraria. Nolte:Celgene, Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Travel grants Other.

scholarly journals A Randomized Phase 2 Study Comparing Acalabrutinib with or without Obinutuzumab in the Treatment of Early Stage High Risk Patients with Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4306-4306 ◽  
Author(s):  
Sameer A. Parikh ◽  
Eli Muchtar ◽  
Betsy Laplant ◽  
Wei Ding ◽  
Sikander Ailawadhi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Research Funding ◽  
Early Stage ◽  
Safety Monitoring ◽  
Data Safety Monitoring Board ◽  
Phase 2 ◽  
Free Survival ◽  
Phase 2 Study ◽  
Very High

Background: The 2018 iwCLL guidelines recommend close observation of early stage CLL pts who do not meet indications for therapy ("watch and wait" strategy). Prior attempts at early therapeutic intervention in unselected early-stage CLL pts using alkylating agents such as chlorambucil and chemoimmunotherapy failed to show a significant benefit; and these therapies were associated with substantial toxicities. The introduction of Bruton tyrosine kinase (BTK) inhibitors has revolutionized the treatment landscape of CLL. The German CLL Study group recently presented results of the CLL12 study which demonstrated a significant improvement in event-free survival (EFS) among untreated early stage high risk CLL pts who received ibrutinib compared to placebo (median EFS not reached vs. 47.8 months, respectively; Langerbeins, EHA, 2019). Acalabrutinib is a more selective second-generation BTK inhibitor that has fewer adverse events in pts with CLL, and has shown equally impressive clinical activity for CLL pts. We are conducting an investigator initiated randomized phase 2 study to compare acalabrutinib with or without obinutuzumab (a glycoengineered anti-CD20 monoclonal antibody approved in the treatment of CLL) among high risk early stage CLL pts. Study Design: All pts with newly diagnosed (<2 years from registration) previously untreated early stage CLL who do not meet the 2018 iwCLL guidelines for initiation of therapy are eligible for enrollment in this study. Pts undergo risk stratification according to the CLL-International prognostic index (CLL-IPI) which consists of the following 5 variables: age >65 years (1 point), Rai stage I-IV (1 point), del17p and/or TP53 mutation (4 points), unmutated immunoglobulin heavy chain (IGHV) genes (2 points), and serum β2-microglobulin >3.5 g/dL (2 points). Pts with high (4-6) and very high (7-10) risk CLL-IPI are randomly (1:1) assigned to acalabrutinib 100 mg orally twice daily (Arm A) or acalabrutinib with obinutuzumab at a standard approved schedule (Arm B). Treatment with acalabrutinib is continued for a minimum of 2 years unless the patient has unacceptable side effects or withdraws consent. Pts with low (0-1) and intermediate (2-3) risk CLL-IPI score are assigned to an observation arm with follow-up once every 6 months for 2 years, and then according to routine clinical practice (Arm C). Endpoints: The primary endpoint of the intervention arms (Arms A and B) is the achievement of minimal residual disease (MRD)-negative complete remission in the bone marrow after 2 years of therapy. MRD is assessed using an 8-color flow cytometry with a detection limit of 0.01%. The primary endpoint of the observation arm (Arm C) is time to first therapy. Secondary endpoints for all arms are: progression-free survival, overall survival, and safety. Statistical design: A randomized trial comparing the experimental arm (acalabrutinib plus obinutuzumab) against the control arm (acalabrutinib alone) will be conducted as described by Rubinstein. A sample size of 36 pts per arm provides 80% power to detect an improvement in MRD-negative complete response rate from 10% to 30%, using a one-sided test at a significance level of 0.10 (EAST 6.4). We anticipate accruing an additional 8 high/very high risk pts (4 in each arm) to account for ineligibility, cancellation, or major treatment violation. The total enrollment for Arms A and B will be 80 pts. We will enroll 40 pts to Arm C; for a total enrollment of 120 pts. Key correlatives: Comprehensive profiling to assess the innate and adaptive immune system in paired peripheral blood and bone marrow will be conducted in all pts registered to Arms A and B at baseline, 12 and 24 months after enrollment. In addition, bone marrow hematopoietic function will be assessed in all pts at these time points. We will employ a CLL focused custom 61-gene panel to estimate tumor mutational burden as well as mutational profiles for each patient at baseline, 12, and 24 month time points, as well at the time of disease progression. Preliminary results: The trial is registered at clinicaltrials.gov NCT03516617. The trial opened to accrual at all three Mayo Clinic sites (Rochester, MN; Jacksonville, FL; and Scottsdale, AZ) in September 2018. Twenty-eight pts have been registered; the baseline characteristics are shown in Table 1. The trial is expected to complete enrollment in September 2020; and the primary analysis will be available in September 2022. Disclosures Parikh: Janssen: Research Funding; AstraZeneca: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; MorphoSys: Research Funding; AbbVie: Honoraria, Research Funding; Acerta Pharma: Research Funding; Ascentage Pharma: Research Funding; Genentech: Honoraria. Ding:DTRM Biopharma: Research Funding; Merck: Research Funding. Ailawadhi:Pharmacyclics: Research Funding; Cellectar: Research Funding; Takeda: Consultancy; Amgen: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Celgene: Consultancy. Kenderian:Novartis: Patents & Royalties, Research Funding; Tolero: Research Funding; Humanigen: Other: Scientific advisory board , Patents & Royalties, Research Funding; Lentigen: Research Funding; Morphosys: Research Funding; Kite/Gilead: Research Funding. Chanan-Khan:Mayo Clinic: Employment; Ascentage: Research Funding; Millennium: Research Funding; Jansen: Research Funding; AbbVie: Research Funding; Xencor: Research Funding; Pharmacyclics: Research Funding; Merck: Research Funding. Kay:Infinity Pharmaceuticals: Other: DSMB; Celgene: Other: Data Safety Monitoring Board; Agios: Other: DSMB; MorphoSys: Other: Data Safety Monitoring Board. OffLabel Disclosure: Drug: Acalabrutinib Purpose: treatment of CLL

An Effective and Tolerable Chemoimmunotherapy Regimen For Relapsed/Refractory and Very-High Risk Chronic Lymphocytic Leukemia Combining Alemtuzumab With Pentostatin and Low Dose Rituximab

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1641-1641
Author(s):  
Clive S. Zent ◽  
Betsy R LaPlant ◽  
Wenting Wu ◽  
Timothy G. Call ◽  
Deborah Bowen ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Adverse Events ◽  
Phase Ii ◽  
Research Funding ◽  
Low Dose ◽  
Lymphocytic Leukemia ◽  
Bulky Disease ◽  
Purine Analogue ◽  
Very High

Abstract Patients with very-high risk (purine analogue refractory and TP53 defective) CLL have limited treatment options. In these patients alemtuzumab can be effective against CLL cells in the circulation and bone marrow, and in combination therapy with fludarabine can be active in patients with bulky disease, but these regimens have a high risk of serious infections. Addition of rituximab to alemtuzumab can also improve efficacy but has limited activity against bulky disease. We conducted a phase II clinical trial to determine the efficacy and toxicity of therapy with pentostatin, alemtuzumab, and low dose higher frequency rituximab (PAR) in patients with relapsed/refractory or progressive CLL with 17p13 deletion. The rituximab schedule was designed to decrease the loss of CD20 expression by circulating CLL cells. Methods This two-stage phase II trial study (NCT00669318) conducted at the Mayo Clinic Rochester and University of Iowa with IRB approval had an accrual goal of 38 evaluable patients. Eligibility required a diagnosis of progressive CLL by standard criteria and either previous treatment for CLL (<4 purine analogue regimens) or 17p13 deletion (17p13-). Exclusion criteria were organ failure, poor performance status (ECOG >3), infection with HIV, hepatitis B, hepatitis C, active autoimmune cytopenia, or alemtuzumab therapy within the past 2 months. Rituximab 20 mg/m2 IV M-W-F started on day 1, alemtuzumab started on day 3 with an escalation of 3-10-30 mg/d SQ and then 30 mg M-W-F from day 8, and pentostatin 2 mg/m2 IV every 2 weeks started on day 8. Peg-G-CSF or GM-CSF was used after each dose of pentostatin and patients received Pneumocystis and Varicella prophylaxis. CMV PCR assays were done weekly during treatment and viremia was treated with either valganciclovir or ganciclovir. Cycle 1 was 5 weeks and subsequent cycles were 4 weeks. At the end of cycle 2 patients with a clinical CR had a CT scan and a bone marrow study with immunohistochemical (IHC) staining for residual CLL cells, and therapy was stopped if there was no radiological or IHC evidence of residual CLL (stringent CR). Patients with residual disease received a 3rd cycle of therapy. Results Forty-one patients were enrolled (July 2008 - February 2013) and all 39 who started therapy were evaluable for response: Median age 61 years (range 47-78), 30 (77%) males, 36 (92%) relapsed/refractory CLL (median prior regimens = 2, range 1-10), 3 (8%) previously untreated, 23 (59%) advanced stage (Rai III-IV), 16 (41%) intermediate stage (Rai I-II). Prognostic factors: FISH (hierarchical classification) 15 (38%) 17p13-, 6 (15%) 11q22-, 5 (13%) 12+, 3 (8%) no defects, 8 (21%) 13q14-, and 2 (5%) other abnormalities, IGHV analysis (n=38) 27 (71%) unmutated (<2%), ZAP-70 (n=37) 28 (76%) positive (>20%). Thirty (77%) patients completed planned therapy (28 had 3 cycles, 2 had 2 cycles with stringent CR). Nine patients received one (n=4) or two (n=5) cycles of therapy because of disease progression or complications. Grade 3-4 hematological adverse events (n=37) at least possibly related to treatment included neutropenia (n=22), thrombocytopenia (n=11), anemia (n=2) and hemolysis (n=2). Non-hematological adverse events (n=17) included infections/neutropenic fever (n=8), fatigue (n=3), and hemorrhage (n=2). CMV reactivation was detected and treated in 14 patients (grade 1-2). No patients died during treatment or from treatment related complications. The overall response rate was 56% (95% CI 40-72) with 4 (10%) CR, 7 (18%) CRi, 11 (28%) PR, 7 (18%) SD, and 10 (26%) PD. Four patients (3 CR and 1 CRi) had IHC negative bone marrow studies. Thirteen (33%) patients have died due to progressive CLL (n = 11), sepsis (n=1), and pneumonia (n=1). Median follow up for surviving patients is 23 months (range 3-55). Seven (18%) patients proceeding to RIC allogeneic transplant were censored for time to next treatment. Twenty-one (54%) patients required therapy for progressive CLL and 7 (18%) have required no further therapy. Median progression free survival was 7 months (95% CI: 5-16), time to next treatment 9 months (95% CI: 6-27) and median overall survival has not been reached. Discussion PAR was effective and tolerable therapy for high-risk CLL. This study suggests that alemtuzumab can be used safely in combination with a purine analogue in a short-duration regimen. Disclosures: Zent: Genentech : Research Funding; Genzyme: Research Funding; Biothera: Research Funding; GlaxSmithKline: Research Funding; Novartis: Research Funding. Off Label Use: Pentostatin therapy for CLL, use of lower doses of rituximab.

PROOF 302: A randomized, double-blind, placebo-controlled, phase III trial of infigratinib as adjuvant therapy in patients with invasive urothelial carcinoma harboring FGFR3 alterations.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. TPS600-TPS600 ◽  
Author(s):  
Sumanta K. Pal ◽  
Siamak Daneshmand ◽  
Surena F. Matin ◽  
Yohann Loriot ◽  
Srikala S. Sridhar ◽  
...  
Keyword(s):  
High Risk ◽  
Adjuvant Therapy ◽  
Urothelial Carcinoma ◽  
Residual Disease ◽  
Genetic Alterations ◽  
Phase Iii ◽  
Potential Candidate ◽  
Double Blind ◽  
Free Survival ◽  
Double Blind Placebo

TPS600 Background: Radical surgery ± cisplatin‐based (neo)adjuvant therapy (NAT) is the mainstay of treatment for invasive urothelial carcinoma of the upper urinary tract (UTUC) or bladder (UBC), but recurrence rates are high. Furthermore, many patients (pts) are unable to receive NAT because of cisplatin ineligibility. Fibroblast growth factor receptor 3 (FGFR3) genetic alterations occur in up to 70% of UTUC and up to 20% of UBC, and may constitute a potential candidate for targeted therapy. Infigratinib (BGJ398), a selective FGFR1–3 inhibitor, has shown promising clinical activity and tolerability in pts with advanced urothelial carcinoma having FGFR3 alterations [Pal et al. Cancer Discov 2018]. PROOF 302 has been designed to investigate the efficacy and safety of infigratinib versus placebo as adjuvant therapy in pts with high-risk invasive urothelial carcinoma and FGFR3 alterations. Methods: PROOF 302 is a randomized, double-blind, placebo-controlled, phase III study of approx. 218 pts. Adults with high-risk invasive UTUC or UBC with FGFR3 genetic alterations (i.e. mutations, gene fusions or translocations) who are ≤120 days following surgical resection and ineligible for cisplatin-based adjuvant chemotherapy or with residual disease after cisplatin- based NAT are eligible. Those who received non cisplatin-based NAT are eligible if they have residual disease and are ineligible for adjuvant cisplatin. Pts receive oral infigratinib 125 mg or placebo (1:1 ratio) once daily on days 1–21 every 28 days for up to 52 weeks or until disease recurrence, unacceptable toxicity or death. Primary endpoint: centrally reviewed disease-free survival (DFS). Secondary endpoints: DFS including intraluminal low-risk recurrence; metastasis-free survival; overall survival; DFS (per investigator); safety and tolerability. Exploratory endpoints include: quality of life; pharmacokinetics; cell-free DNA (cfDNA) and/or RNA for resistance mechanisms. The study will involve approximately 120 centers worldwide. Enrollment is expected to begin in January 2020. Trial registration: EudraCT 2019-003248-63. Clinical trial information: EudraCT 2019-003248-63.

Final analysis of relapse-free survival in a multicenter, double-blind, placebo-controlled trial of seviprotimut-L polyvalent melanoma vaccine after resection of high-risk melanoma.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 10017-10017
Author(s):  
Craig L. Slingluff ◽  
Brent A. Blumenstein ◽  
Karl D. Lewis ◽  
Robert Hans Ingemar Andtbacka ◽  
John Robert Hyngstrom ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Controlled Trial ◽  
Hazard Ratio ◽  
Phase Iii ◽  
P Value ◽  
Relapse Free Survival ◽  
Support Design ◽  
Double Blind ◽  
Free Survival ◽  
Double Blind Placebo

10017 Background: Seviprotimut-L is a vaccine prepared from antigens of 3 human melanoma cell lines, administered with alum. Prior formulations induced T cell and antibody responses and improved survival in a small phase II clinical trial. Part B1 of MAVIS (Melanoma Antigen Vaccine Immunotherapy Study, a three part, Phase III clinical program), was a multicenter, double-blind, placebo-controlled trial to assess efficacy of seviprotimut-L, with the primary endpoint of relapse-free survival (RFS). The goal of Part B1 was to guide design of the pivotal Part B2. Methods: Patients with AJCC v7 stage IIB-III cutaneous melanoma, after surgical resection, age 18-75, ECOG PS 0-1, were randomized 2:1 to seviprotimut-L 40 mcg or placebo, injected subcutaneously every 2 weeks x 5, then monthly x 4, then every 3 months x 9. Patients were stratified by stage (IIB/C, IIIA, IIIB/C). Target enrollment was 325. The study was powered for assessment of RFS, with target hazard ratio (HR) of 0.625, one-sided alpha of 0.10, and power 80%. Final data are presented. Results: 347 patients were randomized. Arms were well-balanced. Treatment-related adverse events (AEs) led to discontinuation in 0.4% and 0%, respectively, for vaccine and placebo arms. There were no treatment-related SAEs. By intent-to-treat (ITT) analysis, RFS was not significantly longer for seviprotimut-L in the full study population but trended toward benefit (HR 0.88). Subgroup analysis based on planned stratification revealed the hazard ratio (HR) for the Stage IIB/IIC subset (randomization stratum, n=111) to be 0.65 (95% CI [0.37, 1.17]), favoring seviprotimut-L. Age can decrease immune competence: RFS was longer with vaccine for patients age <60 overall (N = 191, HR = 0.64 [0.38, 1.08]) and among Stage IIB/C patients (N = 52, HR = 0.32 [0.12, 0.86]). The effect modification interaction p value for age for stage IIB/IIC patients was 0.056. In a multivariable RFS model, for IIB/IIC patients <60 with ulceration (n=38), HR = 0.209 [0.07,0.61]. For overall survival, for patients < 60, HR = 0.41 [0.33,1.14] (n=191, 19 deaths) and for those ≥60, HR = 0.92 [0.39,2.12] (n = 156, 24 deaths). Conclusions: Seviprotimut-L is very well-tolerated. Subgroup efficacy analyses identified populations who may benefit from Seviprotimut-L: those with Stage IIB/IIC melanoma and those under age 60. These data support design of the definitive part B2 of the MAVIS phase III trial to test seviprotimut-L for stage IIB/C patients, with stratification by age and ulceration. Clinical trial information: NCT01546571.

Biochemical relapse in very high-risk prostate cancer after radical prostatectomy and DC-vaccine loaded with tumor RNA, hTERT, and survivin.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 324-324
Author(s):  
Wolfgang Lilleby ◽  
Anne Merete Tryggestad ◽  
Iris Bigalke ◽  
Bjørn Brennhovd ◽  
Karol Axcrona ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Clinical Trial ◽  
Bone Marrow ◽  
Dendritic Cells ◽  
High Risk ◽  
Radical Prostatectomy ◽  
High Risk Prostate Cancer ◽  
Risk Prostate Cancer ◽  
Biochemical Progression ◽  
Very High

324 Background: Patients with very high-risk prostate cancer (VHR-PC) features experience worse outcome after radical prostatectomy. This study was designed to assess biochemical failure and toxicity of adjuvant dendritic cells vaccine (DCV) in prostate cancer patients who are at greatest risk for cancer progression. Methods: Twenty patients with pathological stage pT2 - pT3b and Gleason score 7B-10, pN0, pN+ or pNx were enrolled into the approved study DC-005. The primary end point was clinical failure. Ten patients were tested for disseminated tumor cells (DTCs) to the bone marrow before inclusion to the study. Three patients out of 10 patients had positive DTCs detection in bone marrow. The mean age of the cohort was 63 years (SD 6.9 years), and three patients had postsurgical pN1 status. Eighteen patients had two or more high-risk factors (ISUP grade 5, T3- stage and or PSA > 20 ng/mL). Autologous dendritic cells were transfected with mRNA for hTERT, survivin and tumor mRNA. The DCV product was applied intradermally after curative intended surgery once per week the first months, then once per months the first year, thereafter every 3 months for two years or until biochemical progression (PSA relapse cut-off ≥ 0.3). Results: After 5 years follow-up (FU) 62% (12/20 patients) had not biochemically progressed and with a median FU of 69 months all patients included in the study are alive. Five patients were treated with salvage and one patient with adjuvant radiation treatment, three patients received limited ADT, and three patients are on first line ADT, none of those eight patients have experienced castration resistant prostate cancer. The toxicity was mild with no serious adverse event related to DCV. Conclusions: Adjuvant DCV mitigates the time to biochemical progression. These results appear favorably compared to historical controls in VHR-PC. The clinical outcomes of this study warrants a future enlarged clinical trial. Clinical trial information: NCT01197625.

Therapy With Demethylating Agents Significantly Improves Overall- and AML-Free Survival In Patients With MDS Classified As High-Risk By IPSS Or Very High Risk By IPSS-R and Partial Or Total Monosomy 7-Results From a German Multicenter Study

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2784-2784 ◽  
Author(s):  
Julie Schanz ◽  
Friederike Braulke ◽  
Katayoon Shirneshan ◽  
Kathrin Nachtkamp ◽  
Ulrich Germing ◽  
...  
Keyword(s):  
High Risk ◽  
Supportive Care ◽  
Median Time ◽  
Research Funding ◽  
Risk Group ◽  
Best Supportive Care ◽  
High Risk Group ◽  
Monosomy 7 ◽  
Free Survival ◽  
Very High

Abstract Introduction Total (-7) or partial (7q-) monosomy 7 is frequent in malignant myeloid disorders, observed in around 12% of MDS/AML and up to 40% of therapy-associated MDS/AML. Monosomy 7 is associated with poor outcome, high susceptibility to infections and poor response to chemotherapy. A therapeutic benefit for 5-azacytidine was previously described (Fenaux et al., 2009). The present study was designed to analyze clinical features, prognosis and response to different therapeutic strategies in patients with monosomy 7 in a multicentric, retrospective German cohort study. Patients and methods Currently, 231 patients with MDS/AML following MDS and monosomy 7 were included. Inclusion criteria were defined as follows: Morphologic diagnosis of MDS/AML following MDS, age ≥18 years, bone marrow blast count ≤30% and presence of -7 or 7q-. The data was assembled from centers in Düsseldorf, (n=120; 52%), Cologne (n=38; 17%), Freiburg (n=31; 13%), Göttingen (n=14; 6%), Munich (n=13; 6%), Dresden (n=11; 5%) and Mannheim (n=4; 2%). The median age in the study cohort was 67 years, 65% of patients were males. 29/231 patients (13%) were diagnosed as AML following MDS. MDS/AML was therapy-associated in 24 patients (11%). Regarding IPSS, 38 (19%) were classified as low/intermediate 1 risk and 165 (81%) as intermediate-2/high-risk. According to IPSS-R, 2 (1%) were assigned to the very-low/low risk group, 31 (16%) to the intermediate group, 52 (27%) to the high-risk group and 107 (56%) to the very high risk group. The treatment was classified as follows: Best supportive care (BSC), low-dose Chemotherapy (LDC), high-dose chemotherapy (HDC), demethylating agents (DMA; either 5-azacytidine or decitabine), and others. Results A best supportive care regimen was chosen in nearly half of the patients (49%). The remaining patients received 1-4 sequential therapies (1: 29%; 2: 11%; 3: 10%; 4: 1%). As the first line therapy, 64 patients (54%) received DMA, 24 (20%) an allo-Tx, 9 (8%) HDC, 5 (4%) LDC, and 16 (14%) were treated with other therapies. The best prognosis was observed in patients eligible for allo-Tx: The median OS in transplanted patients was 924 days as compared to 361 days (p<0.01) in patients not eligible for transplantation. In the latter cohort, patients who received DMA at any course of their disease did not differ from those receiving other therapies: The median OS was 468 days in patients treated with DMA as compared to 325 on those with alternative therapies (p not significant) and the median time to AML-transformation was 580 versus 818 days (p not significant), respectively. However, by classifying patients according to IPSS- and IPSS-R, it became obvious that patients with an IPSS high-risk or an IPSS-R very high risk showed a clear benefit from DMA: In the first group, median OS was 444 days in DMA-treated and 201 days in non-DMA-treated patients (p=0.048), in the latter group, median OS 444 days in the DMA-treated and 203 days in the non-DMA treated cohort (p=0.017). Comparable results were observed regarding AML-free survival: Median time to AML was 580 (DMA) vs. 186 (no DMA) days in IPSS high risk patients (p=0.031) and 580 (DMA) vs. 273 (no DMA) days in the IPSS-R very high risk group (p not significant). Conclusions Patients with MDS, partial or total monosomy 7 and a high risk according to IPSS or a very high risk according to IPSS-R show a pronounced benefit when treated with DMA, regarding overall- as well as AML-free survival. Further results from the ongoing data analysis will be presented in detail. The study was supported by research funding from Celgene. Disclosures: Schanz: Celgene: Research Funding. Braulke:Celgene: Research Funding. Germing:Celgene: Honoraria, Research Funding. Schmitz:Novartis: Research Funding; Celegene: Consultancy, Research Funding, Speakers Bureau. Götze:Celgene: Honoraria. Platzbecker:Celgene: Honoraria, Research Funding. Haase:Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding.

Age-Adjusted Co-Morbidity Score - but Not Revised Disease Risk Index - Is Associated with Progression-Free Survival after Intermediate Intensity Double Unit CBT in Adults with Hematologic Malignancies

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3231-3231
Author(s):  
Satyajit Kosuri ◽  
Patrick Hilden ◽  
Sean Devlin ◽  
Yeon Yoo ◽  
Emily Lauer ◽  
...  
Keyword(s):  
High Risk ◽  
Research Funding ◽  
Disease Risk ◽  
Risk Index ◽  
Progression Free Survival ◽  
Hematologic Malignancies ◽  
Free Survival ◽  
Kaplan Meier ◽  
Co Morbidity ◽  
Very High

Abstract Introduction: CB transplantation (CBT) after intermediate intensity conditioning is a less toxic alternative to CBT after high dose myeloablation. However, determinants of progression-free survival (PFS) and the impact of the pre-transplant revised Disease Risk Index (rDRI) and age-adjusted Hematopoietic Cell Transplant Co-morbidity Index (aaHCT-CI) are not established. Methods: We evaluated 2-year PFS in double-unit CBT (dCBT) recipients with hematologic malignancies who were conditioned with a myeloablative but intermediate intensity regimen of cyclophosphamide 50 mg/kg, fludarabine 150 mg/m2, thiotepa 5-10 mg/kg, 400 cGy of TBI with cyclosporine-A/mycophenolate mofetil and no ATG. Eligible patients for this analysis included first allograft recipients aged < 70 years with acute leukemia, MDS, MPD (all < 10% blasts pre-transplant), B-cell NHL or HL. Patients were scored by the rDRI (with FLT-3 positivity categorized as high risk) and aaHCT-CI. PFS was estimated using the Kaplan-Meier method, while Cox proportional hazards regression models were used to assess the association between patient and graft characteristics and PFS. Results: Patients [n = 100, median age 51 years (range 19-70) and median weight 78 kg (32-139) had AML (38 CR1,17 CR2, 1 refractory), ALL (13 CR1, 2 CR2, 1 CR3), MDS (10, blasts ranging 1-10%), MPD (5), B-cell NHL (11 DLBCL or indolent) or HL (2). The rDRI distribution was 6 (6%) low, 55 (55%) intermediate, 34 (34%) high, and 5 (5%) very high whereas the median aaHCT-CI was 3 (range 0-9). The median infused CD34+ cell doses of the larger and smaller units were 1.17 (range 0.35-3.72) and 0.68 (range 0.17-2.18) x 105/kg, respectively, whereas the median 8 allele HLA-match was 5/8 (range 2-8/8). In 42/100 (42%) patients the dCBT grafts were supplemented by CD34+ cell selected haplo-identical peripheral blood stem cells. The cumulative incidence of day 45 neutrophil engraftment was 97% whereas day 100 grade II-IV and III-IV aGVHD were 69% and 15%, respectively, and 1-year chronic GVHD was 6%. Day 180 TRM was 17% and 2-year relapse incidence was 11%. With a median survivor follow-up of 27 months (range 5-91), the 2-year PFS was 66% (95%CI: 56-75). Kaplan-Meier estimates and univariate and multivariate analyses of 2-year PFS by relevant patient and graft variables are shown (Table and Figures). Dividing patients into low-intermediate vs high-very-high rDRI and aaHCT-CI 0-2, 3 and > 4 revealed high aaHCT-CI was associated with worse PFS whereas older age alone and high-very high rDRI were not. The adverse effect of high aaHCT-CI was mediated by an increased risk of TRM early post-transplant. Conclusions: dCBT with intermediate intensity conditioning (Cy/Flu/Thio/TBI 400) is effective in adult patients with high-risk malignancies. Notably, pre-transplant rDRI was not associated with PFS suggesting this therapy is associated with a robust graft-versus-malignancy effect. High aaHCT-CI, however, adversely impacted PFS. These findings support the use of intermediate intensity dCBT in patients with high risk disease without concurrent high aaHCT-CI, and, as with adult donor allografts, new treatment strategies are required for patients with a significant co-morbidity burden. Figure 1. Figure 1. Figure 2. Figure 2. Figure 3. Figure 3. Disclosures Giralt: JAZZ: Consultancy, Honoraria, Research Funding, Speakers Bureau; TAKEDA: Consultancy, Honoraria, Research Funding; CELGENE: Consultancy, Honoraria, Research Funding; AMGEN: Consultancy, Research Funding; SANOFI: Consultancy, Honoraria, Research Funding. Scaradavou:National Cord Blood Program- New York Blood Center: Employment.

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