Phase Ib trial of vactosertib in combination with pomalidomide in relapsed multiple myeloma: A corticosteroid-free approach by targeting TGF-β signaling pathway.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 8039-8039
Author(s):  
Ehsan Malek ◽  
Sunjin Hwang ◽  
Paolo Fabrizio Caimi ◽  
Leland L. Metheny ◽  
Benjamin Kent Tomlinson ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Multiple Myeloma ◽  
Immune System ◽  
Transforming Growth Factor ◽  
Single Agent ◽  
Cell Activity ◽  
Type I ◽  
Phase Ib ◽  
Progression Of Disease ◽  
Grade Iii

8039 Background: Immunosuppression and osteoclast activation are two hallmarks of the bone marrow environment in Multiple Myeloma (MM). Corticosteroids have been used historically as part of anti-myeloma regimens due to their anti-plasma cell activity, however they potentially could suppress immune system and activate osteoclast further; therefore there is an unmet need for corticosteroid-free approaches in the era of emerging anti-cancer immunotherapy modalities. There is an abundance of Transforming Growth Factor-beta (TGF-β), a crucial cytokine in suppression of immune system as well as catabolic bone remodeling, in the MM microenvironment. Vactosertib (Vacto) is a small molecule TGF-β type I receptor inhibitor that has shown single agent activity against myeloma in the syngeneic 5T33MM murine mouse model. Here, we report the phase Ib trial of Vacto in combination with pomalidomide (Pom) without any corticosteroids (NCT03143985). Methods: pts with relapsed MM with at least two lines of therapies enrolled on a 3 + 3 dose escalation design and received Vacto, 60 mg/d, 120 mg/d, 100 mg BID and 200 mg BID in combination with standard dose of Pom (4mg) without corticosteroids. The primary objectives of the study was to assess safety and recommended phase 2 dose. Vacto tablets, taken once or twice daily for 5 days followed by 2 days without treatment, is administered in 28-day cycles, until progression of disease or intolerable toxicity. Results: 15 pts were enrolled on the study (Table). The most common non-hematologic adverse event (AE) was grade II fatigue and pain in one pt, one episode of grade III renal failure that took less than 7 days to get back to baseline on another patient, sinus bradycardia that reversed to sinus rythem and an Afib that was rate controlled with beta blocerks. No grade IV non-hematologic AE was observed. Three pts had grade III hematologic AE, no grade IV hematologic AE. Three out of 15 pts experienced progression of disease (PFS-6: 80%). Conclusions: The phase Ib data shows safety of this agent in combination with Pom. The efficacy assessment (PFS-6: 80%) is higher than the historical control (PFS-6: 20% in randomized Phase II study by Richardson et al. Blood. 2014) with Pom only (PFS-6: 20%) or Pom with corticosteroids (PFS-6: 40%). Further advancement of this agent in clinical trial pipelines for MM is planned. Clinical trial information: NCT03143985. [Table: see text]

scholarly journals Preclinical Studies and Phase I Trial of Vactosertib in Combination with Pomalidomide in Relapsed Multiple Myeloma: A Corticosteroid-Free Approach By Targeting TGF-β Signaling Pathway

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3232-3232
Author(s):  
Ehsan Malek ◽  
Sunjin Hwang ◽  
Marcos de Lima ◽  
Paolo Caimi ◽  
Molly M Gallogly ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Protein Concentration ◽  
Plasma Cells ◽  
Single Agent ◽  
Type I ◽  
Preclinical Studies ◽  
Monoclonal Protein ◽  
Progression Of Disease ◽  
Grade Iii

Multiple Myeloma (MM) is a neoplasm of terminally differentiated plasma cells which proliferate in a permissive bone marrow environment characterized by immunosuppression and osteoclast activation. Although malignant plasma cells do not harbor any mutation in the Transforming Growth Factor-beta (TGF-β) pathway, increased TGF-β secreted by MM cells lead to impaired immune surveillance and promotion of catabolic bone remodeling allowing myeloma progression (Kyrtsonis MC et al. 1998). Here, we conducted preclinical studies in the syngeneic 5T3MM immunocompetent mouse model assessing the efficacy of vactosertib (Vacto), a TGF-β type I receptor antagonist, single agent activity as well as synergistic activity with the third generation immunomodulatory drug, pomalidomide (Pom) and a subsequent corticosteroid-free phase I study to test safety and preliminary efficacy of this combination. (NCT03143985). Methods Preclinical: Mice bearing 5T33MM cells expressing luciferase were treated with Vacto/Pom and the combination for 3 weeks, and evaluated for MM growth by bioluminescence imaging (BLI). Cellular and molecular assays were performed in human RPMI8226 and U266 as well as murine 5T33MM cells via apoptosis, real-time PCR and Western blotting. Peripheral blood monoclonal protein concentration, M-spike, was measured by ELISA. Distal femur trabecular bone structure was assessed by 3D micro-CT. Phase I: pts with relapsed MM with at least two lines of therapies enrolled on a modified Fibonacci 3 + 3 dose escalation design and received escalating dosages of Vacto, 60 mg/d, 120 mg/d and 100 mg BID and 200 mg BID in combination with standard dose of Pom (4mg) without corticosteroids. The study objectives were to assess safety, recommended phase 2 dose, and efficacy of Vacto/Pom in compared to historical control of Pom without corticosteroids (PFS-6: 20% in randomized Phase II study by Richardson et al. Blood. 2014). Vacto tablets, taken daily for 5 days followed by 2 days off, was administered in 28-day cycles, repeated for 6 cycles or until progression of disease or intolerable toxicity. There was no fasting requirement after the first two dose levels. Results: Preclinical: Vacto attenuated the growth and viability of human and murine MM cells by inducing apoptosis and inhibited TGF-β-induced activation of Smad2/3 in MM cells in vitro. In the 5T33MM preclinical model, Vacto inhibited MM progression, as single agent, as measured by peripheral blood monoclonal protein concentration and BLI before and after treatment. Vacto also prolonged survival (Figure-1), prevented weight loss and increased trabecular bone thickness (Figure-2) in mice bearing MM in compare to control. Vacto alone or combination with Pom also attenuated TGF-β activation of Smad2/3, reduced the expansion of CD11b⁺Gr-1⁺ myeloid derived suppressor cells (MDSCs) in the bone marrow, and diminished the population of Foxp3⁺ regulatory T cells in the spleen (Figure-1). Vacto showed anti-myeloma effect at level of 700-750 nM on myeloma cells from three MM pts (Figure-3). Phase I: As of July 30th 2019, 10 pts were enrolled in the study (Table-1). Three pts were refractory to bortezomib and four pts were refractory to lenalidomide. The most common non-hematologic adverse event (AE) was grade II fatigue and pain in one pt with one episode of grade III renal failure that took less than 7 days to get back to baseline, no grade IV non-hematologic AE was observed. Two pts had grade III hematologic AE, no grade IV hematologic AE. Two out of 10 patients experienced progression of disease (PFS-6: 80%) (Figure-4, 5). Conclusions: Vacto is a small molecule TGF-β type I receptor inhibitor that has shown single agent activity against myeloma in the syngeneic 5T33MM murine mouse model, in human myeloma cell lines and primary patient samples. Its effect on the tumor microenvironment is augmented in combination with Pom in the Cereblon-negative immunocompetent murine model. The phase I data shows safety of this agent in combination with Pom. The preliminary efficacy assessment is PFS-6: 80% which is higher than historical control (Richardson et al. Blood. 2014) with Pom only (PFS-6: 20%) or Pom with corticosteroids (PFS-6: 40%). Further advancement of this agent in clinical trial pipelines for MM is planned. Disclosures Malek: Amgen: Speakers Bureau; Adaptive: Consultancy; Janssen: Speakers Bureau; Medpacto: Research Funding; Sanofi: Consultancy; Takeda: Consultancy; Celgene: Consultancy. Hwang:MedPacto: Employment. Metheny:Takeda: Speakers Bureau; Incyte: Speakers Bureau. OffLabel Disclosure: Experimental therapeutics: Vactosertib

PrE0807 phase Ib feasibility trial of neoadjuvant nivolumab (N)/lirilumab (L) in cisplatin-ineligible muscle-invasive bladder cancer (BC).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS4594-TPS4594
Author(s):  
Petros Grivas ◽  
Maneka Puligandla ◽  
Suzanne Cole ◽  
Kevin Dale Courtney ◽  
Robert Dreicer ◽  
...  
Keyword(s):  
Type I Error ◽  
Single Agent ◽  
Pathologic Complete Response ◽  
Neoadjuvant Treatment ◽  
Complete Response ◽  
Upper Urinary Tract ◽  
Feasibility Trial ◽  
Type I ◽  
Phase Ii Trials ◽  
Phase Ib

TPS4594 Background: Neoadjuvant cisplatin-based chemotherapy before radical cystectomy (RC) improves outcomes but ~50% of patients (pts) are cisplatin-unfit. Anti-PD(L)1 agents can prolong overall survival (OS) in platinum-resistant advanced BC and have shown high pathologic complete response rate (pCR) and safety as single agent in phase II trials in the neoadjuvant setting. The combination of anti-PD-1 and anti-KIR agents is feasible and very attractive based on complementary and non-overlapping roles in regulating adaptive and innate immune response as well as impacting the function CD8+ T and NK-cells. Higher CD8+ T cell density (TCD) at RC tissue correlates with longer OS. We hypothesize, that combining anti-PD1 (N) with anti-KIR (L) is safe and feasible as neoadjuvant therapy in cisplatin-unfit pts and results in high CD8+ TCD at RC. Methods: Phase Ib multi-institutional trial evaluating 2 doses (4 weeks apart) of N alone or N+L in 2 cohorts; pts will be assigned sequentially to N (Cohort 1), and if there is no negative safety signal after the first 12 pts, subsequent pts will be assigned to N+L (Cohort 2). Key eligibility: cT2-4aN0-1M0 stage, ≥20% tumor at TURBT, adequate organ function, no autoimmune disease within 2 years, no concurrent invasive upper urinary tract carcinoma or other active cancer. Primary endpoint: safety based on CTCAE v5.0 measured as the rate of ≥G3 treatment related adverse events (AE). Key secondary endpoints: CD8+ TCD absolute and % change between TURBT and RC, % of pts who do not get RC within 6 weeks after neoadjuvant treatment due to treatment-related AE, % pCR, recurrence-free survival, and evaluation of biomarkers in tumor tissue, blood, urine. Rates of ≥Grade 3 AE with neoadjuvant treatment will be reported along with 90% exact binomial CI. In Cohort 1, maximum CI width is 0.51; in Cohort 2, it is 0.36. Our hypothesis is that the change in CD8+ TCD between TURBT and RC will be about 3 CD8+ T cells / 100 tumor cells within HPF. Up to 43 pts will be enrolled for 36 eligible, treated pts (12:N, 24:N+L). Cohort 1 and 2 have 81% and 98% power, respectively, to detect the hypothesized difference with 1-sided type I error rate of 0.05. Trial is open to accrual in US. Clinical trial information: NCT03532451.

Avelumab and cetuximab in combination with FOLFOX in patients with previously untreated metastatic colorectal cancer (MCRC): The phase II AVETUX-CRC trial (AIO KRK 0216).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS3620-TPS3620 ◽  
Author(s):  
Alexander Stein ◽  
Mascha Binder ◽  
Carsten Bokemeyer ◽  
Salah Eddin Al Batran ◽  
Axel Hinke ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Mismatch Repair ◽  
Phase Ii ◽  
Type I Error ◽  
Single Agent ◽  
Objective Response ◽  
Progression Free Survival ◽  
Type I ◽  
Translational Research Program ◽  
Clinical Trial Information

TPS3620 Background: Inhibition of the PD-1/L1 axis has shown to improve survival as single agent in a variety of tumor types. The efficacy of single agent PD-1/L1 inhibition in patients with treatment refractory MCRC seems to be limited to hypermutated tumors characterized by mismatch repair deficiency. 1st line chemotherapy (e.g. FOLFOX) with cetuximab for patients with RAS/BRAF wildtype MCRC result in objective response rates of about 60%, thus substantial antigen release will likely occur triggering immune control. Furthermore, the induction of immunogenic cell death has been recently shown for cetuximab-based regimen. Thus, the evaluation of FOLFOX and cetuximab in combination with avelumab in 1st line MCRC is of particular interest. Methods: AVETUX is a single arm exploratory phase II investigator initiated trial. Patients with RAS/BRAF wildtype MCRC will be included independent of mismatch repair status to receive mFOLFOX6 and cetuximab in combination with avelumab (10mg/kg from day 1 of cycle 2 onwards). Treatment with avelumab is limited to a maximum of 18 months. Primary endpoint is 12month progression-free survival rate, which should be increased from 40% to 57%, with type I error of 10% and 80% power, leading to a sample size of 43 patients. An early stopping rule will be applied in case of an increase in toxicity after the first 15 patients received at least two months of treatment. The trial is flanked by a large translational program including immunoprofiling to determine and correlate the respective immune response signatures with clonal dynamics (RAS/EGFR). Recruitment will start in 11 German sites early 2017. Clinical trial information: EudraCT No 2016-004434-26. Conclusion: The AVETUX trial will determine the feasibility and early efficacy of FOLFOX and cetuximab combined with avelumab in 1st line MCRC. The translational research program will shed light on the potential mode of action of this novel combination. Clinical trial information: 2016-004434-26.

A Phase I Study of CHR-2797, an Orally Active Aminopeptidase Inhibitor in Elderly and/or Treatment Refractory Patients with Acute Myeloid Leukemia or Multiple Myeloma.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 443-443 ◽  
Author(s):  
Faith Davies ◽  
Gert Ossenkoppele ◽  
Pierre Zachee ◽  
Richard Noppeney ◽  
Alan Burnett ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Phase I ◽  
Active Metabolite ◽  
Myeloid Leukemia ◽  
Single Agent ◽  
Once Daily ◽  
Grade Iii ◽  
Acute Myeloid

Abstract Background. CHR-2797 is a novel, orally bioavailable agent which displays potent, tumor cell-selective, anti-proliferative properties. It is an inhibitor of Zn++-dependent aminopeptidases and generates signs of amino acid deprivation in sensitive cells, decreased protein synthesis and an increase in the level of the pro-apoptotic protein, NOXA. CHR-79888 is an active metabolite of CHR-2797. Methods. This was an open label, single agent, dose escalating phase I salvage study to assess tolerance, MTD/DLT, activity, and pharmacokinetics of CHR-2797 in patients with hematological malignancies. Elderly patients and/or relapsed patients with acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and multiple myeloma (MM) were eligible. Patients were treated with escalating once daily doses (60–180 mg) for up to 84 days or until progressive disease (PD). Clinical responses were assessed by monthly bone marrow aspirates in AML/MDS patients and by M-protein levels in MM patients. Results. Sixteen adults (4 women, 12 men) of median age 70 yrs, (range 45–84 yrs) were accrued between May 2006 and Jan 2007: 13 patients with AML, 1 with MDS, and 2 with MM. Thirteen patients finished the dose finding phase of 28 days and 6 patients continued for at least 84 days. CHR-2797 was well tolerated and, except for one patient with grade III ALT elevation, no grade III/IV drug related non-hematological toxicity was observed during the first 28 days of treatment. Two patients on 180 mg developed DLT that was considered drug related: >75 percent reduction in platelet count. CHR-2797 had no influence on hemoglobin or neutrophils in this trial. Overall the most frequently reported adverse events were thrombocytopenia (6.7%), diarrhea (4.5%), dizziness (3.9%), and fatigue (3.9%). Five AML patients died in the first 3 months of the trial or within 4 weeks of discontinuing CHR-2797: 3 due to disease progression and 2 following a MI (not related to drug). Bone marrow studies revealed complete responses (< 5% blasts in bone marrow) in 3/12 AML patients after 1–3 months of therapy (60 and 130mg), one of which was also a cytogenetic response. One of the 2 responding patients on 130 mg was evaluated as a CRp at 3 months; this patient was in remission for 3 months following platelet recovery after the drug was stopped. One further AML patient (60 mg) became completely transfusion independent and remained so for 6 weeks. Good exposure to CHR-2797, including levels of the active metabolite CHR-79888 has been observed on days 1 and 28 with a terminal half life (for 79888) of 8– 11 hours. Conclusions. Oral once daily CHR-2797 in AML/MDS/MM patients with adverse prognostic risk was well tolerated. MTD for maintenance therapy was reached at 180 mg. Single agent CHR-2797 therapy showed encouraging clinical activity (incl. 3/12 CRs) in these elderly and poor risk AML patients who were able to continue therapy for at least 28 days. Because of the favorable results a phase II study with CHR-2797 in advanced AML is currently in progress.

Phase I Trial of CCI-779 (Temsirolimus) and Weekly Bortezomib in Relapsed and/or Refractory Multiple Myeloma

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3696-3696 ◽  
Author(s):  
Irene M. Ghobrial ◽  
Nikhil Munshi ◽  
Robert Schlossman ◽  
Stacey Chuma ◽  
Renee Leduc ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Peripheral Neuropathy ◽  
Phase I ◽  
Median Time ◽  
Single Agent ◽  
Mtor Inhibitors ◽  
Hematologic Toxicity ◽  
Cell Transplant ◽  
Dose Escalation Study ◽  
Progression Of Disease

Abstract BACKGROUND: Preclinical studies have demonstrated activity of the combination of mTOR inhibitors and bortezomib in Multiple Myeloma (MM). Single agent mTOR inhibitors (including CCI-779) have shown modest activity in MM. The objective of this phase I dose-escalation study was aimed to determine the maximum tolerated dose (MTD) as well as the activity of the combination of CCI-779 (Wyeth Pharmaceutical, PA) and bortezomib (Millennium Pharmaceutical, MA) in patients with relapsed and/or relapsed, refractory MM. METHODS: Four cohorts (3 patients each) were planned, with dosing of bortezomib 1.3 or 1.6mg/m2 (days 1, 8, 15 and 22) every 35 days (1 cycle) and CCI-779 15 or 25 mg IV (days 1, 8, 15, 22 and 29) every cycle. Dexamethasone was not permitted during therapy. NCI CTCAE v3.0 was used for toxicity assessment; Dose limiting toxicity (DLT) was defined as any grade (G) 3 or greater non-hematologic toxicity related to therapy, G4 neutropenia for 7 d and/or neutropenic fever, or platelets <10,000/mm3 on >1 occasion despite transfusion, inability to receive day 1 dose for cycle 2 due to toxicity. Response was assessed by modified EBMT criteria. Prior therapy with bortezomib or CCI-779 was allowed. Patients remained on therapy until progression of disease or intolerance. RESULTS: Twenty patients (13 men and 7 women) have been treated to date, of these 5 were on cohort 3 and 9 on cohort 4. The median age was 58 yrs (range: 48–81), and median number of prior therapies was 5 (range: 1–10), including prior stem cell transplant with autologous, or allogeneic transplant, bortezomib, lenalidomide, thalidomide, and combination chemotherapy. All of the patients had received prior bortezomib therapy except for one patient. One DLT was observed in cohort 4 (death due to sepsis and septic shock grade 5, possibly related to therapy and underlying myeloma). Cohort 4 was expanded and no further DLTs were observed. MTD was therefore declared at CCI-779 of 25 mg and bortezomib of 1.6mg/m2. Grade (G) 3 and 4 related toxicities included thrombocytopenia (G3 in 35%, G4 in 25%) leucopenia and neutropenia G3 in 25% with no G4 toxicity, G3 anemia in 15%, and nausea, vomiting, viral infection, hyponatremia, pneumonia, hyperglycemia, mucositis, fatigue, and renal insufficiency in 2% of patients. No significant (G2 to G4) peripheral neuropathy has been seen thus far. No anticoagulant prophylaxis has been required, and no DVTs have occurred. The median time of follow up is 6 months (1–13 months). Response was assessed after completion of 2 cycles of therapy. In 15 evaluable patients, the overall response rate (CR+PR+MR) was 33% (5 patients), including 1nCR and 4 MR. The median time of therapy of patients who achieved response was 8 months (2–12 months). All responses occurred in patients who have received prior bortezomib. Six patients had stable disease for a median of 7 months (6–11 months), and 4 patients showed progression of disease (at 3–5 months post initiation of therapy). Responses occurred in the early cohorts indicating activity of these agents even at lower doses. Conclusions: The combination of CCI-779 25 mg and weekly bortezomib 1.6mg/m2 weekly is active and well tolerated, and minimal peripheral neuropathy to date. The ORR of 33% in heavily pretreated patients with MM, including prior bortezomib therapy, is encouraging. The phase II trial using the MTD of this combination is currently being initiated and enrollment is ongoing.

A Phase II Clinical Trial of the Anti-EGFR Antibody Cetuximab in Patients with Refractory or Relapsed Multiple Myeloma: Final Results,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3965-3965
Author(s):  
Bastian von Tresckow ◽  
Boris Böll ◽  
Dennis A. Eichenauer ◽  
Denissa Peine ◽  
Stefan Knop ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Multiple Myeloma ◽  
Side Effects ◽  
Partial Response ◽  
Stable Disease ◽  
Clinical Benefit ◽  
Single Agent ◽  
Acneiform Rash ◽  
Grade 3 ◽  
Egfr Antibody

Abstract Abstract 3965 INTRODUCTION: So far, monoclonal antibodies have not yielded convincing therapeutic success in multiple myeloma (MM). Therefore, the discovery of an effective targeted antibody against MM would open new perspectives for patients with relapsed or refractory MM and for the combination with established therapies. Cetuximab is an anti-epidermal growth factor receptor (EGFR) antibody. EGFR is also expressed on multiple myeloma (MM) plasma cells and bone marrow stromal cells. Recently, the inhibition of EGFR by small molecule inhibitors has been shown to induce apoptosis in primary myeloma cells revealing a synergistic effect with dexamethasone. Therefore, the anti-EGFR antibody cetuximab might be of clinical benefit in the treatment of MM, especially in combination with dexamethasone. Here we show the final results of the first clinical trial with an anti-EGFR antibody in MM. METHODS: Cetuximab was administered once weekly in standard dose to patients with refractory or relapsed MM who had previously received at least one line of prior treatment including autologous stem cell transplant (ASCT). Patients who still were candidates for ASCT were not included. Dexamethasone 20 mg on day 1–3 of each cycle was added starting week 5 in case of tumor progression or week 9 if no partial response (PR) or complete response (CR) was achieved with cetuximab alone. Planned treatment duration was 16 weeks (primary endpoint) with the possibility to prolong treatment in case of stable disease (SD) or response. RESULTS: In total, 15 patients have been enrolled. Seven patients were treated for a minimum of 16 weeks and 5 of those patients received cetuximab for at least 28 weeks. One patient received cetuximab treatment as single agent for more than one year. Thrombocytopenia, hyponatremia and acneiform rash were the most common CTC grade 3 or 4 side effects. Acneiform rash CTC grade 1 occurred in all patients and 3 patients suffered from acneiform rash CTC grade 3. After 16 weeks (primary endpoint) cetuximab in combination with dexamethasone induced 4 responses (3 minimal responses (MR) and 1 partial response (PR)) and achieved stable disease (SD) in 1 patient. Cetuximab as single agent induced SD in 2 patients. This results in an intention-to-treat overall response rate (ORR; CR+PR+MR) of 27% and a clinical benefit rate (at least SD) of 47%. Five of the 15 patients included did not receive the planned 16 weeks of treatment due to progressive disease (PD); three patients stopped treatment due to intolerable side effects. Six patients were treated more than 16 weeks: 1 patient received cetuximab as single agent and had SD more than a year and 5 patients continued treatment with cetuximab and dexamethasone in combination. CONCLUSIONS: Cetuximab is feasible and safe in MM patients. It demonstrated moderate efficacy in highly pre-treated patients, especially in combination with dexamethasone. Due to its unique mode of action and favorable side effect profile, cetuximab should be evaluated as combination partner for established substances such as bortezomib or lenalidomide to increase response rates both in therapy naive and in refractory patients. Disclosures: No relevant conflicts of interest to declare.

Anti-ABCG2 Monoclonal Antibody in Combination with Paclitaxel-Nanoparticles Against Cancer Stem-Like Cell Activity in Multiple Myeloma

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 5044-5044
Author(s):  
Cuiping Yang ◽  
Jun Dou ◽  
Baoan Chen ◽  
Yunyu Sun ◽  
Yonglu Wang ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Monoclonal Antibody ◽  
Conflicts Of Interest ◽  
Severe Combined Immunodeficiency ◽  
Single Agent ◽  
Cell Activity ◽  
Bone Lesions ◽  
M Cell ◽  
Cycle Arrest ◽  
Synergistic Induction

Abstract Abstract 5044 In spite of the past efforts and progress made in treatment multiple myeloma (MM), most MM patients have eventually relapsed and died of the cancer. Cancer stem cells (CSCs) are considered responsible for continued growth and recurrence of cancer. The purpose of this study was to investigate the effects of anti-ABCG2 monoclonal antibody (mAb) in combination with paclitaxel-Fe3O4 nanoparticles (PTX-NPs) on CD138−CD34−MM cancer stem-like cells (MM CSCs) isolated from MM cell line JJN3. In our results, the MM CSCs expressed higher levels of the ABCG2 transporter, exhibited high proliferative, clonogenic and migratory potency, and demonstrated strong drug resistance and tumorigenicity when compared to non-CD138−CD34−MM cells. Incubation of mAb with PTX-NPs remarkably induced G/M cell cycle arrest, and increased synergistic induction of MM CSC apoptosis compared with incubation with PTX-NPs or PTX or mAb alone. More importantly, mAb in combination with PTX-NPs led to a significant reduction in the tumor volume, to a visible alleviation of murine lytic bone lesions and to a markedly increased survival rate in contrast to using a single agent in MM CSCs when it was transplanted to nonobese diabetic/severe combined immunodeficiency mice. Our study is the first to report on the anti-MM CSC activities by PTX-NPs as single agent or used together with mAb to treat MM. This finding from our study provides a rationale for future clinical trials. Disclosures: No relevant conflicts of interest to declare.

Efficacy and Safety of Salvage Therapy Using Carfilzomib for Relapsed or Refractory Multiple Myeloma Patients: A Multicentre Retrospective Observational Study

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5371-5371
Author(s):  
Eli Muchtar ◽  
Moshe Gatt ◽  
Ory Rouvio ◽  
Chezi Ganzel ◽  
Evgeni Chubar ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Multiple Myeloma ◽  
Partial Response ◽  
Drug Combination ◽  
Salvage Therapy ◽  
Odds Ratio ◽  
Single Agent ◽  
Dose Schedule ◽  
Advisory Board ◽  
Refractory Multiple Myeloma

Abstract Introduction: Carfilzomib has been established in previous years as a treatment for patients with relapsed and/or refractory multiple myeloma (RR-MM). A retrospective multicentre study to evaluate the clinical use of carfilzomib for RR-MM outside of a clinical trial setting was conducted by our group. Methods: All consecutive patients with RR-MM who received carfilzomib-containing salvage therapy outside of a clinical trial between March 2013 and April 2015 were included in this study. For the response and survival analyses, patients were included only if they received at least one full cycle of carfilzomib and response evaluation was available. Carfilzomib was used either as a single agent or in combinations with other drugs, according to the treating physician's choice. Per manufacturer's recommendations, carfilzomib was given by intravenous infusion over 10-30 minutes on days 1, 2,8,9,15,16 of 28-days cycle. The recommended dose of carfilzomib was 20 mg/m2 on days 1 and 2 in cycle 1, which was increased on subsequent administrations to 27 mg/m2 (the 20/27 mg/m2 schedule), provided that the previous dose was well tolerated. Doses, however, were modified according to the treating physician's discretion. Results: One-hundred and thirty-five patients were included. The median age at carfilzomib initiation was 67.9 years (range, 41-88). Male and female patients were equally balanced. Eastern Cooperative Oncology Group (ECOG) performance status 3 or 4 was evident in 14.8% of patients. All patients were previously exposed to bortezomib and 93% to lenalidomide as well. The median time from last treatment to carfilzomib was 5.5 months (range, 0.3-43). Patients had received a median of 3 lines of therapy prior to carfilzomib (range, 1-7). The median number of administrated cycles of carfilzomib was 4 (range, 0.3-22). The majority of patients (79.3%) received carfilzomib according to the 20/27 mg/m2 dose schedule. The remaining patients received carfilzomib either at a dose that did not exceed 20 mg/m2 (11.8%) or at maximal dose higher than 27 mg/m2 (8.9%, mostly as a 20/27/56 mg/m2 dose schedule). Carfilzomib was administrated as a single agent in 5.1% of patients or combined with a second agent in 43% of them. Additionally, 46.7% of patients received carfilzomib as part of a three-drug combination and 5.2% of patients as part of four-drug combination or more. In comparison to patients who received two-drug combination (or carfilzomib alone), patients who received three-drug (or more) combination were younger, with less prior treatment lines and higher baseline haemoglobin, albumin and eGFR (Table I). There was also pre-selection by lower frequency of ImIds resistance in the three-drug combination sub-group, but bortezomib resistance was similar between sub-groups. One hundred and twenty three patients (91.1% of patients) were evaluable for response and survival analysis. The overall response rate was 48.8%, with one patient (0.8%) achieving complete response (CR), 30 patients (24.4%) attaining very good partial response (VGPR) and 29 patients (23.6%) with partial response (PR). Additionally, 15 patients (12.2%) achieved minimal response (MR), reaching a clinical benefit response (CBR) rate of 61%. A multivariate analysis revealed three parameters negatively impact the likelihood of achieving response: bortezomib resistance (odds ratio 0.33, 95% CI 0.12-0.94, p=0.03); lenalidomide resistance (odds ratio 0.31, 95% CI 0.11-0.91, p=0.03), and albumin <3.5 g/dL (odds ratio 0.32, 95% CI 0.14-0.71 p=0.005). The median duration of response was 8.3 months, significantly higher in patients receiving three-drug combination and in patients presenting without extramedullary disease. The median progression free survival (PFS) and overall survival for the entire cohort were 4.9 months (95% CI 3.9-6.9) and 19.3 months (95% CI 9.4-not yet reached), respectively. Toxicity was manageable, although treatment-related death was seen in 5% of patients. Conclusion: In the setting of progressive multiple myeloma, carfilzomib in a combination regimens yields an effective results with a manageable toxicity. Drug resistance is an important factor in determining response quality to carfilzomib. Disclosures Raanani: Ariad: Other: Advisory Board; Pfizer: Other: Advisory Board; BMS: Other: Advisory Board; Novartis: Other: Advisory Board, Research Funding.

Low-Dose Dexamethasone Does Not Abrogate the Immunomodulatory Effects of Lenalidomide and Both Reactivate the Impaired Immune System of High-Risk Smoldering Multiple Myeloma Patients

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2955-2955
Author(s):  
Bruno Paiva ◽  
Maria-Victoria Mateos ◽  
Luis Ignacio Sánchez-Abarca ◽  
Maria Belen Vidriales ◽  
Lucia Lopez-Corral ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Immune System ◽  
High Risk ◽  
T Lymphocytes ◽  
Nk Cells ◽  
Low Dose ◽  
Single Agent ◽  
Immunomodulatory Effects ◽  
Activation Markers ◽  
Cd8 T Lymphocytes

Abstract Introduction: While dexamethasone (Dex) has been commonly used in the treatment of multiple myeloma (MM), its immunosuppressive effect is becoming a matter of concern with the advent of immune-based therapies. One example is the combination of lenalidomide and Dex (LenDex) because it has been reported that Dex abrogates the immunomodulatory effects of Len; however, most of the studies have been performed in vitro, using high-doses of Dex, and in small series of relapsed patients previously exposed to other drugs. Methods: Because the potentially antagonist effect of Dex may represent a dilemma in the design of clinical trials, here we aim to shed light into the question about whether or not low-dose Dex abrogates the immunomodulatory effect of Len by studying the phenotypic profile of T-lymphocytes, NK-cells and dendritic cells (DCs) of 31 previously untreated high-risk smoldering MM (SMM) patients enrolled in the Quiredex trial at baseline, after 3 and 9 cycles of LenDex, and during maintenance with Len as single-agent. Results: Patients with high-risk SMM showed at baseline normal numbers of CD4 and CD8 T-lymphocytes as well as CD56dim and CD56bright NK-cells compared to age-matched healthy individuals. By contrast, they displayed an increment of TCRγδ positive T-lymphocytes (P=.02) and Tregs (P=.04), as well as an altered distribution of BDCA-1 positive myeloid DCs (P=.02) and tissue macrophages (P=.06). Moreover, the expression levels of activation markers (CD25, CD28 and CD54) as well as Th1-related markers (CD195, IFN-γ, TNF-α, or IL-2) were significantly inferior in T-lymphocytes from high-risk SMM patients. A significantdown-regulation of proliferation-related markers (CD119 and CD120b) was also noted. To assess the combined effect of LenDex in T-lymphocytes and NK-cells, we compared the immune status of the 31 high-risk SMM patients at baseline vs. after 3 and 9 cycles of LenDex. Interestingly, TCRγδ positive T-lymphocytes as well as Tregs were further increased with LenDex; conversely, CD4 T-lymphocytes were significantly decreased at the end of induction. There was a marked shift on the distribution of antigen-related maturation subsets induced by LenDex, and reflected by a significant increase of central memory CD4 (P<.001) and effector memory CD8 (P<.001) T-lymphocytes. Accordingly, CD4 and/or CD8 T-lymphocytes showed an increased expression of activation markers (CD69, CD25, CD28, and CD54), together with an up-regulation of the Th1 related chemokine CCR5 (CD195) and increased cytokine production of IFNγ, TNFα, and IL-2. NK-cells showed an up-regulation of the activation marker HLA-DR (P<.001), the ADCC associated receptor CD16 (P≤0.005), and the adhesion molecules CD11a (P≤0.001) and CD11b (P≤0.005) after 3 and 9 courses of LenDex. The percentage of cells in S-phase progressively increased from baseline vs. 3 and 9 cycles of LenDex for CD4 (P<0.001) and CD8 (P<0.001) T-lymphocytes as well as NK-cells (P<0.001). Most interestingly, high-risk SMM patients treated with LenDex and without disease progression showed higher numbers of functionally active T-lymphocytes as compared to those progressing to MM. To address the question whether Dex antagonizes Len, we compared the immune profile of 13 patients with PB samples collected at cycle 9 of induction vs. during maintenance (single-agent Len at least 3 months after Dex discontinuation). No significant differences were observed for the absolute numbers of all cell populations analyzed. From the total 63 phenotypic parameters analyzed, only 7 were found to be differently expressed. Namely, the expression of CD94, CD154 and CD212 positive T-lymphocytes as well as CD11a in T-lymphocytes and NK-cells were down-regulated during maintenance. Conclusions: Our results, obtained from a carefully selected population of patients without previous exposure to anti-MM therapy and with available longitudinal samples after consecutive cycles of LenDex, shed new light on the synergy between lenalidomide and dexamethasone which, at low doses, does not abrogate the immune modulatory effects of lenalidomide here analyzed. Accordingly, high-risk SMM patients have an impaired immune system that could be re-activated with LenDex, and support the value of therapeutic immunomodulation to delay the progression to MM. Disclosures Paiva: Millenium: Consultancy; BD Bioscience: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Onyx: Consultancy; Sanofi: Consultancy; EngMab AG: Research Funding; Binding Site: Consultancy. Mateos:Takeda: Consultancy; Celgene: Consultancy, Honoraria; Onyx: Consultancy; Janssen-Cilag: Consultancy, Honoraria. San Miguel:Celgene: Honoraria; Bristol-Myers Squibb: Honoraria; Janssen-Cilag: Honoraria; Sanofi-Aventis: Honoraria; Millennium: Honoraria; Novartis: Honoraria; Onyx: Honoraria.

A phase Ib dose escalation study of combined inhibition of IDO1 (GDC-0919) and PD-L1 (atezolizumab) in patients (pts) with locally advanced or metastatic solid tumors.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 105-105 ◽  
Author(s):  
Howard A. Burris ◽  
Michael S. Gordon ◽  
Matthew David Hellmann ◽  
Patricia LoRusso ◽  
Leisha A. Emens ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Single Agent ◽  
Locally Advanced ◽  
Cell Activity ◽  
Median Number ◽  
Sepsis Syndrome ◽  
Open Label ◽  
Dose Escalation Study ◽  
Phase Ib

105 Background: GDC-0919, a small molecule inhibitor of indoleamine-2,3-dioxygenase 1 (IDO1), reduces tryptophan catabolism and kynurenine production within the tumor microenvironment that may promote normal effector T cell activity and an immunogenic state. IDO1 inhibition may complement targeting of PD-L1 with atezolizumab. Methods: A Phase Ib, open-label, study assessed safety, pharmacokinetics (PK), pharmacodynamics (PD), and anti-tumor activity (RECIST v1.1) of GDC-0919 and atezolizumab in pts with locally advanced or metastatic solid tumors. Pts were given escalating doses of GDC-0919 (50-1000 mg orally twice daily, for 21 days) and atezolizumab (1200 mg IV, every 3 weeks) using a standard 3+3 design. Results: As of 14Dec2016, 52 pts were treated in 6 cohorts of GDC-0919 plus atezolizumab. The median number of prior systemic therapies was 3 (range 1-9); 2 pts received prior immunotherapy. Pts received a median of 4 cycles of GDC-0919 and atezolizumab (range 1-17). No MTD was identified. Across all dose levels, 1 DLT was observed (Grade [G] 3 sepsis syndrome at GDC-0919 200 mg); no G4/5 AEs were attributed to study treatment. G3+ AEs, regardless of causality were reported in 34 (65%) pts. Related G3 AEs were reported in 7 (13%) pts, included nausea, rash, sepsis syndrome, fatigue, and pneumonitis. Two pts (4%) had AEs leading to treatment discontinuation, related in 1/2 (G3 pneumonitis). Combination PK was consistent with single agent observations and supports BID dosing of GDC-0919. Peripheral PD showed dose-dependent decreases in plasma kynurenine, consistent with systemic modulation of IDO1. Preliminary efficacy data from 45 pts with ≥ 1 on-treatment tumor assessments included 4 patients (9%) with partial response and 11 (24%) pts with stable disease. Conclusions: The combination of GDC-0919 and atezolizumab was generally well-tolerated and demonstrated peripheral IDO1 modulation and preliminary efficacy in a heterogeneous patient population during dose escalation. The study is currently enrolling pts with select tumor types in expansion cohorts to assess tumor PD and combination efficacy. Clinical trial information: NCT02471846.

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