scholarly journals Safety and Early Efficacy Analysis of a Novel Combination of the PARP Inhibitor Veliparib (ABT-888) Plus Bendamustine and Rituximab in Patients with Lymphoma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1739-1739
Author(s):  
John F. Gerecitano ◽  
Paul Hamlin ◽  
Steven M. Horwitz ◽  
Matthew J Matasar ◽  
Alison J. Moskowitz ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
B Cell ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Parp Inhibitor ◽  
Safety Data ◽  
B Cell Lymphoma ◽  
B Cell Lymphomas

Abstract Background: PARP is overexpressed in many malignancies, and can protect tumor cells from chemotherapy related genetic damage. The PARP inhibitor veliparib (V) enhances the cytotoxicity of several alkylating agents. Since bendamustine (B) is an alkylator with promising clinical activity in a variety of lymphoid malignancies and some solid tumors, we have executed a phase 1b trial combining V with B in patients with solid tumors, lymphomas and multiple myeloma. The dose escalation portion of this study was reported in 2013, and established an MTD of 300 mg bid V in combination with B. We are now completing a cohort expansion of V plus B and rituximab (R) in patients with B-cell lymphomas, concluding this phase 1 trial. We present updated results from lymphoma patients included in the dose escalation portion of the study and new data on the cohort expansion in patients with B-cell lymphomas. Methods: Patients with relapsed solid tumors, lymphoma and multiple myeloma with no standard curative options were eligible for enrollment to the dose escalation portion of this trial. Patients with B-Cell lymphoma (excluding Burkitt and Burkitt-like lymphomas) were treated with B 90mg/m2 IV days 1 and 2, V 300 mg PO bid x7 days and R 375 mg/m2 on day 1 of each 28 day cycle. Planned treatment duration was 6 cycles, with the option of additional cycles in cases of clinical benefit. The cohort expansion was designed to treat 6 patients at the Maximum Tolerated Dose (MTD) of V and B to assess for tolerability with the addition of R. Cohorts were planned with reduced doses of V if dose limiting toxicities (DLT) were seen in >2/6 patients in the first cohort. Results: During the dose escalation phase, 8 patients with lymphoma were treated with B + V. The median number of prior therapies was 4 (range 1-10), and 3 patients received prior B. Six out of 7 evaluable patients responded, with 4 achieving complete remission (CR) and 3 partial remission (PR). Five responding patients have progressed, while one mantle cell lymphoma patient who achieved a CR remains in remission. Median Progression Free Survival in patients with lymphoma treated in the dose escalation phase is 7 months (range 1.8 – 17.4). Five of 6 patients with B-cell lymphoma have been enrolled to the expansion cohort portion of this study (in which R is added to B+V). Toxicities reported in expansion are similar to those from the escalation portion of the study, and include nausea, vomiting and myelosuppression. No DLTs have yet been observed, although one patient did not complete cycle 1 V due to grade 1 nausea before optimal antiemetics could be instituted. All toxicities to date have been grade 1 or 2, with the exception of grade 3 lymphopenia in one patient. Efficacy and additional safety data will be updated in the final presentation. Conclusions: R 375 mg/m2 added to the MTD of V plus B is tolerable in patients with B-cell lymphoma. To date, no additional DLTs have been seen after addition of R to the regimen. This regimen has shown efficacy in lymphoma, although it is unclear if V adds benefit to R/B and a phase II trial will be needed to differentiate the benefit of V. Disclosures Hamlin: Gilead, Spectrum, Seattle Genetics, Genentech: Consultancy; Spectrum, GSK, Jansen and Jansen/Pharmacyclics, Portola, Seattle Genetics: Research Funding. Horwitz:Celgene: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Spectrum: Research Funding; Infinity: Research Funding; Kiowa-Kirin: Research Funding; Amgen: Consultancy; Bristol-Myers Squibb: Consultancy.

Veliparib (ABT-888), Bendamustine, and Rituximab (VBR) Is Well Tolerated and Efficacious in Patients with Lymphoma: Final Analysis of a Phase 1b Clinical Trial of VB and a Cohort Expansion of Vbr in Patients with B-Cell Lymphoma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2691-2691
Author(s):  
Jacob D Soumerai ◽  
Andrew D Zelenetz ◽  
Craig H Moskowitz ◽  
Anas Younes ◽  
Maria Lia Palomba ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Multiple Myeloma ◽  
B Cell ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
B Cell Lymphomas ◽  
Phase 1B ◽  
Grade 3

Abstract Background: PARP is overexpressed in many malignancies and protects against chemotherapy-induced genetic damage. The PARP inhibitor veliparib enhances the cytotoxicity of alkylating agents. Bendamustine is an alkylator with activity in several lymphoid malignancies, multiple myeloma, and solid tumors. Bendamustine plus rituximab (BR) is highly active in indolent B-cell lymphomas, with overall (ORR) and complete response rates (CRR) of 90-92% and 41-60%, respectively. We therefore completed a phase 1b trial of veliparib plus bendamustine (VB) in patients with solid tumors, lymphoma and myeloma, as well as a cohort expansion of veliparib, bendamustine and rituximab (VBR) in patients with CD20+ B-cell lymphomas. We report here final response data with 10.5 months (median) of follow up for all patients with lymphoma included in this trial. Methods: Patients with relapsed solid tumors, lymphoma and multiple myeloma with no standard curative options were eligible for the dose escalation portion of this trial. We have previously reported the results of the dose escalation portion, wherein MTD was established at level 6 (veliparib 300mg PO BID plus bendamustine 90 mg/m2). In the cohort expansion, patients with CD20+ B-cell lymphoma (excluding Burkitt and Burkitt-like lymphoma) were treated with bendamustine 90mg/m2 IV days 1 and 2, veliparib 300 mg PO bid on days 1-7 and rituximab 375 mg/m2 on day 1 of each 28-day cycle, for a total 6 cycles. Results: Lymphoma histologies (n=15) were FL (7), DLBCL, transformed FL, or Richter's transformation (4), classical Hodgkin lymphoma (3) and MCL (1). Eight patients received VB in the dose escalation portion and 7 received VBR in the cohort expansion (all CD20+ NHL). Fourteen patients were evaluable for response. One patient with FL in the dose escalation cohort was withdrawn for inability to swallow study drug. Median age was 66 (26-82), median number of prior therapies was 3 (1-10), 7 were refractory to prior therapy, 3 received prior bendamustine, and all patients with CD20+ disease received prior rituximab. Among 7 patients who received VB in the dose escalation cohort, ORR and CRR were 5/7 (71%) and 4/7 (57%). Median PFS is 6.9 months (range 1.6 - 31.3), and 4 of 5 responding patients have progressed. Among 7 patients who received VBR in the cohort expansion, ORR and CRR were 6/7 (86%) and 5/7 (71%). Median PFS is not yet reached at 12.4 months (range 2.0-17.1), and 2 of 6 responding patients have progressed. All patients with FL achieved CR (including 1 VB, 5 VBR). Toxicities in the cohort expansion are similar to those from the dose escalation study. DLTs were grade 4 anemia and grade 3 nausea, hypertension and hyperhidrosis. No DLTs were seen in the cohort expansion. Among all 42 patients treated on study with either VB or VBR, grade ≥3 toxicities were lymphopenia (85.7%), anemia (19%), neutropenia (11.9%), thrombocytopenia (9.5%), leukopenia (7.1%), fatigue (4.8%), nausea (4.8%), sepsis (4.8%), anorexia (2.4%), transaminitis (2.4%), duodenal hemorrhage (2.4%) and hyperhidrosis (2.4%). Conclusions: VBR is tolerated and efficacious in patients with B-cell lymphoma, particularly among patients with follicular lymphoma. These data warrant further investigation of VBR in a phase II clinical trial. Disclosures No relevant conflicts of interest to declare.

scholarly journals Phase 1 Study of the Parp Inhibitor E7449 As a Single Agent in Patients with Advanced Solid Tumors or B-Cell Lymphoma

2014 ◽  
Vol 25 ◽  
pp. iv151 ◽  
Author(s):  
R. Plummer ◽  
D. Dua ◽  
N. Cresti ◽  
A. Suder ◽  
Y. Drew ◽  
...  
Keyword(s):  
B Cell ◽  
Solid Tumors ◽  
Cell Lymphoma ◽  
Phase 1 ◽  
Parp Inhibitor ◽  
Single Agent ◽  
B Cell Lymphoma ◽  
Advanced Solid Tumors ◽  
Phase 1 Study

A Phase I Open-Label, Multi-Dose Escalation Study of the Dual Syk/Jak Inhibitor PRT062070 (Cerdulatinib) in Patients with Relapsed/Refractory B Cell Malignancies

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3103-3103
Author(s):  
Manish Patel ◽  
Paul Hamlin ◽  
Donald K Strickland ◽  
Anjali Pandey ◽  
Greg Coffey ◽  
...  
Keyword(s):  
Steady State ◽  
B Cell ◽  
Dose Escalation ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Phase 1 ◽  
B Cell Lymphoma ◽  
Markers Of Inflammation ◽  
Equity Ownership ◽  
Grade 3

Abstract Introduction: Preclinical studies of the Syk-mediated B-cell receptor pathway and Jak-mediated cytokine pathways have demonstrated a potential therapeutic advantage for the dual inhibition of both Syk and Jak kinases in the treatment of B-cell malignancies. Cerdulatinib (PRT062070) was identified from a chemistry screen as a potent and selective inhibitor of Syk, Jak1, Jak3, and Tyk2, with minimal activity against Jak2. Cerdulatinib is efficacious in rodent models of B-cell lymphoma and autoimmune disease (Coffey et al., ASH 2012) and has demonstrated anti-tumor activity in genetically diverse B-cell lymphoma cell lines that is greater than that of Syk- or Jak- selective inhibitors alone (Ma et al., ASH 2013). Methods: This Phase 1 3+3 dose escalation study is evaluating cerdulatinib, given continuously on either a once daily (QD) or twice daily (BID) schedule, for relapsed/refractory chronic lymphocytic leukemia (CLL) or B-cell non-Hodgkin lymphoma (NHL). The primary objective is to determine the maximum tolerated dose (MTD) of cerdulatinib in patients with CLL or NHL. Secondary objectives are to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of cerdulatinib and to make a preliminary assessment of antitumor activity. Toxicity is graded according to the National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) v4. Clinical response is evaluated according to published criteria (Hallek et al., Blood 2008:111:5446-5456; Cheson et al., J. Clin. Oncol. 2012: 25:579-586). The level of inhibition of Syk and Jak is determined using a variety of whole blood assays measuring signaling via receptors for the B-cell antigen, IL2, IL4, IL6, and GM-CSF. Serum markers of tumor burden, including CCL3, CCL4, and other markers of inflammation, are also being measured. Results: As of 4 August 2014, twelve patients have been enrolled in once daily dose cohorts of 15 mg QD, 30 mg QD, and 45 mg QD. No dose-limiting toxicities have been reported. Grade ≥3 adverse events (AEs), regardless of causality, were: Grade 3 anemia (n=1), Grade 3 neutropenia (n=1), Grade 3 fatigue (n=1), Grade 3 hypotension (n=1), Grade 3 AST increased (n=1), Grade 3 hematochezia (n=1), and Grade 5 Pneumocystis pneumonia (PCP; n=1). The patient who experienced PCP pneumonia was a 76 year old male with CLL who had received prior therapy with bendamustine and rituximab. Cerdulatinib is well-absorbed with an average terminal elimination half-life at steady state of 14 hours. Selective inhibition of Syk and Jak in whole blood assays was observed post-treatment, with IC25-IC50 (Cmin to Cmax at steady-state) against these targets achieved at the 15 mg dose level, and IC50-IC80 (Cmin to Cmax at steady-state) achieved at the 30 mg and 45 mg doses. Reductions of >50% in serum markers of inflammation, as well as in CCL3 and CCL4, were noted at all dose levels post-treatment. Two patients treated at the 15 mg dose (1 CLL, 1 follicular lymphoma [FL]) remained on study for >230 and >200 days, respectively, with stable disease (SD) prior to disease progression. One patient treated at the 30 mg dose (diffuse large B-cell lymphoma [DLBCL], who did not respond to prior R-CHOP therapy), remained on study with SD for 140 days. One patient treated at the 30 mg dose (CLL) experienced a >60% decrease in peripheral lymphocyte count prior to coming off study for PCP pneumonia. Another patient treated at the 30 mg dose (CLL) experienced early lymphocytosis and a 33% reduction in lymph node size at the end of Cycle 2 and remains on study in Cycle 3. One patient treated at the 45 mg dose (FL) experienced a 40% decrease in lymph node size at the end of Cycle 4 and remains on study in Cycle 5. Conclusions: Cerdulatinib has been well tolerated in the initial cohorts of this Phase 1 study, with no dose-limiting toxicities and preliminary evidence of anti-tumor activity. Dose escalation continues and Phase 2 expansion cohorts are planned in CLL, DLBCL and FL. Disclosures Hamlin: Gilead, Spectrum, Seattle Genetics, Genentech: Consultancy; Spectrum, GSK, Jansen and Jansen/Pharmacyclics, Portola, Seattle Genetics: Research Funding. Strickland:SCRI Development Innovations: Employment. Pandey:Portola Pharmaceuticals, Inc.: Employment; Portola Pharmaceuticals, Inc.: Equity Ownership. Coffey:Portola Pharmaceuticals: Employment, Equity Ownership. Leeds:Portola Pharmaceuticals, Inc.: Employment. Levy:Portola Pharmaceuticals: Employment; University of Michigan: Patents & Royalties. Curnutte:Portola Pharmaceuticals, Inc.: Employment, Equity Ownership; Sea Lane Biotechnologies: Consultancy; 3-V Biosciences: Equity Ownership. Wagner-Johnston:Gilead: Consultancy; Gilead: Speakers Bureau; Celgene: Research Funding. Flinn:Portola Pharmaceuticals, Inc.: Research Funding.

The Response Evaluation Criteria in Solid Tumors Can be Substituted for the International Workshop Criteria?: Comparison Using Japan Clinical Oncology Group Study JCOG0203 for Untreated Indolent B-Cell Lymphoma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4779-4779
Author(s):  
Kenichi Miyamoto ◽  
Takashi Watanabe ◽  
Hideaki Kitahara ◽  
Masashi Wakabayashi ◽  
Kenichi Nakamura ◽  
...  
Keyword(s):  
B Cell ◽  
Malignant Lymphoma ◽  
Solid Tumors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
International Workshop ◽  
B Cell Lymphoma ◽  
Complete Response ◽  
Kappa Coefficient ◽  
Response Evaluation

Abstract Introduction: The International Workshop Criteria (IWC) has been used for response evaluation in malignant lymphoma since 1999. In contrast, the Response Evaluation Criteria in Solid Tumors (RECIST) has been used for most solid tumors since 2000. The IWC is more complicated than RECIST, partly because it requires calculating the sum of the product of bidimensional diameters of the target lesions, whereas RECIST is based on unidimensional assessment of target lesions. If RECIST can be demonstrated to be more valid and precise than the IWC for malignant lymphoma, RECIST would be the substitute for IWC even for malignant lymphoma. The objective of this study was to evaluate whether RECIST could be substituted for the IWC using data from the JCOG0203 trial, a phase II/III study of R-CHOP-21 versus R-CHOP-14 in untreated, advanced-stage indolent B-cell lymphoma where the superiority of R-CHOP-14 in progression-free survival (PFS) was not shown (hazard ratio [HR], 0.92; 95% CI, 0.68-1.25; one-sided log-rank p = 0.30) (J Clin Oncol 2011;29:3990-8). Methods: Three hundred patients aged 20-69 with stage III or IV indolent B-cell NHL were enrolled in the JCOG0203 trial between 2002 and 2007. Patients ineligible after the central pathological review (CPR) or patients with no target lesions for RECIST were excluded from this analysis. We calculated the kappa coefficient to evaluate the degree of agreement between IWC and RECIST. RECIST would be considered better in cases of a kappa coefficient of ≥0.7 because this indicates that both are in good agreement and RECIST is less complicated. If the kappa coefficient is <0.7, RECIST would be considered discordant with IWC. We evaluated which criteria were more predictive for PFS. In particular, criteria that can show a good separation of PFS, namely, the lower point estimate of the hazard ratio (HR) of a complete response (CR, including complete response and unconfirmed CR [CRu]) vs. a non-CR, is defined as more useful criteria. The landmark-time analysis was applied to PFS counted from day 168, when response status (CR vs. non-CR) for all patients was fixed. Results: Overall, 269 patients were included in this analysis, 14 patients were ineligible by the CPR and 17 patients without target lesions for RECIST were excluded.The median age was 54 years, and 46.8% of the patients were men. Two-hundred fifty-six (95.2%) were diagnosed as having follicular lymphoma and 8 (3.0%) with extranodal marginal zone B-cell lymphoma. According to the Follicular Lymphoma International Prognostic Index, 85 (31.6%), 112 (41.6%), and 72 (26.8%) patients were classified as being at low, intermediate, and high risk, respectively.Based on the IWC, 207 patients (77.0%) had a CR/CRu, 54 (20.1%) a partial response (PR), 3 (1.1%) had stable disease (SD), 4 (1.5%) had progressive disease (PD), and 1 (0.4%) was not evaluable (NE). Based on RECIST, 120 (44.6%) had a CR, 137 (50.9%) had a PR, 6 (2.2%) SD, 4 (1.5%) had PD, and 2 (0.7%) were NE. The kappa coefficient between IWC and RECIST was 0.342 (95% CI, 0.261-0.424), indicating poor agreement. Subsequently, we calculated the HR (CR vs. non-CR) of PFS for each criterion with 264 patients in the landmark analysis. The HR of the IWC (0.473: 95% CI, 0.330-0.677, log-rank test p < 0.001) was lower than that of RECIST (0.635: 95% CI, 0.454-0.888, p = 0.0075). In terms of overall survival, the HR (CR vs. non-CR) was 0.500 (95% CI, 0.223-1.119, p = 0.0856) and 0.471 (95% CI, 0.197-1.130, p = 0.0843) according to IWC and RECIST, respectively. Conclusion: RECIST cannot be substituted for the IWC in untreated, advanced-stage indolent B-cell NHL. Although fluorodeoxyglucose-positron emission tomography should be included in the standard response criteria currently used, introduction of unidimensional assessment is not recommended. Disclosures Maruyama: Takeda: Honoraria; Janssen: Honoraria. Tobinai:Chugai Pharma: Research Funding; Ono Pharmaceutical: Research Funding; Abbvie: Research Funding; Takeda: Honoraria, Research Funding; Kyowa Hakko Kirin: Research Funding; Eisai: Honoraria, Research Funding; Janssen Pharmaceuticals: Honoraria, Research Funding; Celgene: Research Funding; HUYA Bioscience: Honoraria; Mundipharma KK: Honoraria, Research Funding; SERVIER: Research Funding; Zenyaku Kogyo: Honoraria; GlaxoSmithKline: Research Funding; Daiichi Sankyo Co., Ltd.: Consultancy. Tsukasaki:Daiichi Sankyo Co., Ltd.: Consultancy; Takeda: Research Funding.

scholarly journals Adding Etoposide to R-CHOP (R-CHOEP) Does Not Significantly Increase the Risk of Secondary Neoplasms in Patients with Aggressive B-Cell Lymphoma - Results from Randomized Phase 3 Trials of the German Lymphoma Alliance (GLA)

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 5-6
Author(s):  
Fabian Frontzek ◽  
Marita Ziepert ◽  
Maike Nickelsen ◽  
Bettina Altmann ◽  
Bertram Glass ◽  
...  
Keyword(s):  
B Cell ◽  
Solid Tumors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Advisory Board ◽  
First Line ◽  
Phase 3 ◽  
Increased Risk ◽  
Aggressive B Cell Lymphoma

Introduction:Considering the increasing numbers of lymphoma patients (pts) surviving long-term, late effects of current treatment strategies such as secondary (sec) malignancies gain increasing importance. Many treatment regimens used in pts with lymphoma (R-CHOEP, DA-EPOCH-R, BEACOPP) include etoposide, a cytotoxic agent reported to increase sec leukemias. In order to further investigate the role of etoposide in inducing sec malignancies in pts with aggressive lymphoma we analyzed the R-MegaCHOEP trial (Schmitz et al., Lancet Oncology 2012) where young, high-risk pts with aggressive B-cell lymphomas had received R-CHOEP or R-MegaCHOEP, a regimen containing very high doses of etoposide (4g/m2). We compared rates of secondary tumors to incidences found in young patients treated with R-CHOP only. Methods:We analyzed 1536 pts aged 18-60 years with aggressive B-cell lymphoma treated in the prospective phase 3 trials FLYER (NCT00278421; n=588, median observation time (OT)=66 months), UNFOLDER (NCT00278408; n=695, median OT=72 months) and MegaCHOEP (NCT00129090; n=253, median OT=112 months) to compare the cumulative incidences of sec neoplasms. We performed a competing risk analysis for time from randomization to occurrence of sec malignancy (myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) or other) according to first-line therapy with R-CHOP (n=1283) vs. R-CHOEP (n=127) vs. R-MegaCHOEP (n=126). We used a cause-specific hazard model adjusted for gender, age (&gt;50 vs. &lt;= 50 years) and radiotherapy. Results:Adjusting for competing events, we found sec MDS/AML in 0.3% of pts treated with R-CHOP, in 1% of pts treated with R-CHOEP and in 2% of pts following treatment with R-MegaCHOEP. Cause-specific hazard ratios showed a trend for increased risk for sec AML following R-MegaCHOEP in comparison to R-CHOP (HR 5.2, 95%CI (1.0; 27.5), p=0.052) while R-CHOEP did not significantly increase the incidence of sec AML (HR 1.4, 95%CI (0.1; 14.0), p=0.777). Male gender and age &gt;50 years showed a trend for increasing sec AML. We found very similar incidences of sec solid tumors (not MDS/AML) affecting 4% of pts treated with R-CHOP or R-MegaCHOEP and 6% of pts following R-CHOEP regimen. The only factor significantly increasing the risk of sec solid tumors was age &gt;50 years (HR 2.6, 95%CI (1.5; 4.3), p&lt;0.001). Conclusions:This analysis shows that sec malignancies represent rare events in younger patients with aggressive B-cell lymphoma, even after extreme dose-escalation of etoposide. Compared to standard R-CHOP, 8 cycles of R-CHOEP were not associated with increased risk of sec AML or solid tumors thus remaining an attractive first-line treatment for young high-risk pts with DLBCL. Disclosures Haenel: Amgen, Novartis, Roche, Celgene, Takeda, Bayer:Honoraria.Truemper:Janssen:Consultancy;Mundipharma:Research Funding;Nordic Nanovector:Consultancy;Roche:Research Funding;Seattle Genetics:Research Funding;Takeda Europe:Consultancy, Research Funding.Held:MSD:Consultancy;Acrotech, Spectrum:Research Funding;Amgen:Research Funding;BMS:Consultancy, Other: Travel Grants, Research Funding;Roche:Consultancy, Other: travel grants, Research Funding.Borchmann:Bristol Myers Squibb:Research Funding;Takeda:Research Funding.Dreyling:Celgene:Consultancy, Research Funding, Speakers Bureau;Roche:Consultancy, Research Funding, Speakers Bureau;Beigene:Consultancy;Janssen:Consultancy, Research Funding, Speakers Bureau;Novartis:Consultancy;Abbvie:Research Funding;Astra Zeneca:Consultancy;Bayer:Consultancy, Speakers Bureau;Gilead:Consultancy, Research Funding, Speakers Bureau.Viardot:Roche:Honoraria, Other: advisory board;Kite/Gilead:Honoraria, Other: advisory board;Novartis:Honoraria, Other: advisory board;Amgen:Honoraria, Other: advisory board.Kroschinsky:Riemsser:Research Funding;Roche:Consultancy, Honoraria, Other: Support of parent study and funding of editorial support;Gilead:Consultancy;BMS/Celgene:Consultancy, Honoraria;Sandoz:Research Funding.Ott:NIH:Consultancy, Other: Co-inventor on a patent related to the MCL35 assay filed at the National Institutes of Health, United States of America..Lenz:Bayer:Consultancy, Honoraria, Research Funding, Speakers Bureau;Janssen:Consultancy, Honoraria, Research Funding, Speakers Bureau;Novartis:Consultancy;Gilead:Consultancy, Honoraria, Research Funding, Speakers Bureau;AQUINOX:Research Funding;AstraZeneca:Consultancy, Honoraria, Research Funding;Celgene:Consultancy, Honoraria, Speakers Bureau;Verastem:Research Funding;Morphosys:Consultancy, Honoraria, Research Funding;Roche:Consultancy, Honoraria, Research Funding, Speakers Bureau;Agios:Research Funding;BMS:Consultancy.Schmitz:Riemser:Honoraria;Takeda:Honoraria;Janssen:Research Funding;Bristol-Myers Squibb:Current equity holder in publicly-traded company.

Patient-Derived Xenograft Model in B-Cell Lymphoma: A Platform for a Personalized Clinical Trial

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1839-1839
Author(s):  
Taylor Bell ◽  
Hui Zhang ◽  
Makhdum Ahmed ◽  
Hui Guo ◽  
Carrie J Li ◽  
...  
Keyword(s):  
B Cell ◽  
Tumor Cells ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Drug Resistant ◽  
B Cell Lymphomas ◽  
Advisory Committees ◽  
Patient Derived Xenograft ◽  
Pdx Model

Abstract Background: Imprecise correlation of treatment response in established cell line and cells obtained from patients (i.e., patient-primary) limits the preclinical investigation of novel compounds. Similarly, the "xenograft" models wherein human cancer cell lines are transplanted into immunocompromised mice do not represent the full spectrum of cancers. However, Patient-derived xenograft (PDX) mouse models have been shown to recapitulate the diversity of growth, metastasis, and histopathology of the original tumor. Based on our previously established mantle cell lymphoma (MCL) PDX model, we developed other B-cell lymphoma PDXs recapitulating tumor pathological and clinical characteristics, progression and response to therapeutic agents, this will provide an indispensable model system towards personalized treatment for B-cell lymphoma. Methods: We developed 34 PDX models with an implanted fetal bone chip for several B-cell lymphomas including marginal zone lymphoma (MZL), follicular lymphoma (FL), Burkitt's lymphoma (BL), and diffuse large B-cell lymphoma (DLBCL), and MCL. We tested the in vitro efficacy of a panel of drugs among freshly isolated tumor cells from patients and tumor cells from the PDX models. We also generated a drug-resistant MCL PDX model, compared the effect of targeted drugs on the tumor burden in the drug-resistant model and identified potential therapeutic opportunity with drug combinations. We validated combination therapy in vivoand conducted next generation sequencing (NGS) using a 1,212 gene panel (OncoPlus®) on DNA from primary patient cells. Results: We collected clinical samples from 34 patients with several types of B-cell lymphomas including MCL (n=21), DLBCL (n=3), FL (n=2), BL (n=1), and MZL (n=2). Of the 34 patients, 18 (53%) were newly diagnosed and untreated clinically, 11 (32%) patients were relapsed after treatment with 1-3 chemotherapy or targeted therapy treatments, and 5 (15%) patients were treated with one-dose therapy before sample collection. All of the tumor cells, from both the patient and PDXs, showed the same drug response pattern. Consecutive ibrutinib administration to PDX mice from PT1 during G4 induced the development of an ibrutinib-resistant tumor. The cell viability of isolated PDX tumor cells treated with ibrutinib was not significantly different between G1 and G2 nor was it different between G5 and G6 (p>0.05). In addition, histological features were consistent with patient tumor histology. Furthermore, whole exome sequencing revealed fidelity between the patient and PDX tumor cells as well as between subsequent generations of the PDX. [B1] We[Z2] engrafted a patients tumor cells into NSG-hu mice to create an MCL-bearing PDX mouse model (PT28-PDX). G2 PDX cells were isolated and treated with a panel of drugs. We found that G2 PDX cells were most sensitive to bortezomib (BTZ) (Velcade®). Growth inhibition of the G2 PDX cells was significantly higher with BTZ compared to ibrutinib (p=0.002) and cells were most sensitive to BTZ compared with other agents (p≤ 0.002). Based on this finding, the patient was treated with Velcade®, rituximab and dexamethasone and responded to treatment. However, the G3 PDX became resistant to BTZ. She was then treated with a 1 cycle of rituximab and cytarabine. Soon after, we initiated three-drug combination treatment with lenalidomide (Len), rituximab (RTX) and dexamethasone (DEX) in PDX G4. Len+RTX+DEX significantly prolonged mouse survival indicating that this could be an effective regimen for this patient after BTZ relapse. As guided by the PDX, PT28 underwent Len+RTX+DEX regimen and her peripheral lymphocytosis disappeared demonstrating response. Conclusions: The PDX model with implanted fetal bone chip is a valid experimental platform that recapitulates tumor characteristics of B-cell lymphomas. Leveraging the PDX platform to identify and select drugs that are likely to be efficacious for individual patients and subsequently administering the promising agents to those who relapse after an initial therapy is the next milestone. Disclosures Wang: BeiGene: Research Funding; Asana BioSciences: Research Funding; Juno Therapeutics: Research Funding; Pharmacyclics: Research Funding; Celgene: Research Funding; Onyx: Research Funding; Kite Pharma: Research Funding; Acerta Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals A Phase I Study of Selinexor and R-ICE in Patients with Relapsed/Refractory Aggressive B-Cell Lymphomas

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 7-8
Author(s):  
Sarah C. Rutherford ◽  
John N. Allan ◽  
Jia Ruan ◽  
Richard R. Furman ◽  
Kristy Richards ◽  
...  
Keyword(s):  
Phase I ◽  
B Cell ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
B Cell Lymphomas ◽  
Dosing Schedule ◽  
Large B Cell Lymphoma ◽  
Car T ◽  
Additional Therapy

Introduction: Patients (pts) with aggressive B-cell lymphomas who are relapsed or refractory to frontline therapy are typically treated with regimens including R-ICE (rituximab, ifosfamide, carboplatin, etoposide) followed by autologous stem cell transplant (ASCT) in responding pts. A minority of pts are cured with this approach, and the majority have poor outcomes. Selinexor is an oral, selective inhibitor of nuclear export, which activates tumor suppressor proteins and blocks translation of proteins that can contribute to chemoresistance, including MYC and BCL2. We conducted a phase I trial of selinexor plus R-ICE in pts with relapsed/refractory aggressive B-cell lymphomas. Methods: This phase I study used a 3+3 design with dose expansion. Eligible pts had diffuse large B-cell lymphoma (DLBCL), double hit lymphoma (DHL), and indolent lymphoma transformed to DLBCL. Treatment with 1 prior regimen administered with curative intent was required. Central nervous system (CNS) involvement was excluded. A separate cohort enrolled pts with Richter's transformation (RT) from chronic lymphocytic leukemia; there was no requirement with regard to prior therapies for this group. Selinexor was initially dosed at 40 mg (DL-1), 60 mg (DL1) and 80 mg (DL2) on days (d) -5, -3, 1, 3, and 5 and R-ICE on d1-3 of a 21-d cycle. Because of CNS toxicity thought to be primarily related to ifosfamide, the protocol was amended so that R-ICE was given on d1-3 and selinexor following completion of ifosfamide on d3, 5, and 7 of each cycle. After 2 cycles, responding pts were eligible to receive SCT or chimeric antigen receptor (CAR) T-cell therapy at discretion of treating physician. Dose limiting toxicity (DLT) period was cycle 1 and included grade (gr) 4 febrile neutropenia; gr 4 neutrophils for ≥7d; gr 4 platelets for ≥10d; gr 3 nausea, vomiting, diarrhea, or fatigue lasting &gt;3d; or gr ≥3 non-hematologic toxicities except alopecia, fatigue or electrolyte abnormalities correctable with supportive care. Results: 22 pts enrolled with median age 67 (range 34-79). 64% were male and 36% female. Stage was III-IV in 72%. IPI was intermediate to high risk in 77%. Diagnosis was DLBCL NOS in 12, DHL in 4, transformed indolent lymphoma in 2, primary mediastinal large B-cell lymphoma in 1, and RT in 3. 7 pts were treated on the initial dosing schedule. In the first group at DL1, 0/3 pts had DLT. At DL2, 2/2 pts had DLT (gr 3 altered mental status, AMS). In the second group at DL1, 1/2 pts had DLT (gr 3 AMS). The dosing schedule was then modified as noted above. 12 DLBCL pts were treated on the modified dosing schedule. At DL1, 2/3 pts had DLT (gr 5 sepsis, gr 4 platelets ≥10d). At DL-1, 1/6 pts had DLT (gr 3 abdominal infection). Selinexor 40 mg was declared the recommended phase 2 dose (RP2D) and 3 pts were enrolled in an expansion. 3 pts with RT were treated on the modified dosing schedule; 2 received selinexor and neither had DLT at DL1. Median number of cycles of selinexor plus R-ICE was 2 (range 1-3). Most common gr 3-4 toxicities were cytopenias and hyponatremia. Most common non-hematologic toxicities of all grades were hyponatremia, fatigue, transaminitis, and nausea. Of 21 pts who received selinexor plus R-ICE, objective response rate (ORR) was 71% with 7 complete responses (CR), 8 partial responses (PR), and 3 stable disease (SD). 5 underwent SCT (3 autologous, 2 allogeneic) and 8 received CAR T-cells. Those who underwent transplant have not required additional therapy to date. 4 complete responders did not receive ASCT in part related to difficulty mobilizing stem cells; 3 have not required additional therapy with follow up of 26, 46, and 46 months. At the RP2D in the DLBCL cohort (n=9), ORR was 78% with 4 CR, 3 PR, and 2 SD. Conclusions: We report the first data on the combination of selinexor, which is now FDA-approved as a single agent in relapsed/refractory DLBCL, and chemotherapy in pts with aggressive B-cell lymphomas. We identified a dosing schedule of selinexor with R-ICE (40 mg on d3, 5, and 7) that is worthy of further study based on initial efficacy, with attention to CNS toxicity and impact on stem cell collection. Disclosures Rutherford: Karyopharm: Consultancy, Research Funding; Regeneron: Research Funding; Seattle Genetics: Consultancy; LAM Therapeutics: Research Funding; Kite: Consultancy; Juno: Consultancy; AstraZeneca: Consultancy; Celgene: Consultancy; Dova: Consultancy; Genentech/Roche: Research Funding; Heron: Consultancy. Allan:Acerta, Genentech, Abbvie, Sunesis, Ascentage, Pharmacyclics, Janssen, AstraZeneca, BeiGene: Consultancy; Celgene, Genentech, Janssen, TG Therapeutics: Research Funding; Abbvie, Janssen, AstraZeneca, Pharmacyclics: Honoraria. Ruan:Celgene: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Research Funding; Kite Pharma: Consultancy; Juno: Consultancy; BMS: Consultancy, Research Funding. Furman:Oncotarget: Consultancy; Loxo Oncology: Consultancy; Verastem: Consultancy; Beigene: Consultancy; AstraZeneca: Consultancy, Research Funding; Acerta: Consultancy; Abbvie: Consultancy; Genentech: Consultancy; Incyte: Consultancy; Janssen: Consultancy, Speakers Bureau; TG Therapeutics: Consultancy, Research Funding; Sunesis: Consultancy; Pharmacyclics: Consultancy. Cerchietti:BMS: Research Funding. Gergis:Incyte: Speakers Bureau; Merck: Speakers Bureau; Astellas: Consultancy, Speakers Bureau; Kite: Speakers Bureau; Mesoblast: Other: Ad Board; Jazz: Other: Ad board, Speakers Bureau. Leonard:Regeneron: Consultancy; BMS/Celgene: Consultancy; Roche/Genentech: Consultancy; Epizyme: Consultancy; Bayer: Consultancy; Gilead/Kite: Consultancy; Karyopharm: Consultancy; GenMab: Consultancy; ADC Therapeutics: Consultancy; AstraZeneca: Consultancy; MEI Pharma: Consultancy; Sutro: Consultancy; Miltenyi: Consultancy. Martin:Bayer: Consultancy; Beigene: Consultancy; Kite: Consultancy; Incyte: Consultancy; Cellectar: Consultancy; Morphosys: Consultancy; Regeneron: Consultancy; Sandoz: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Karyopharm: Consultancy, Research Funding; Teneobio: Consultancy; I-MAB: Consultancy.

scholarly journals Pharmaocogenomic Characterization of MCL-1 Inhibitor Response and Resistance in Aggressive B-Cell Lymphomas

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 20-21
Author(s):  
Michelle Wang ◽  
Tao Li ◽  
Yuan Ren ◽  
Bijal Shah ◽  
Tint Lwin ◽  
...  
Keyword(s):  
B Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Lymphoid Cells ◽  
Synergistic Activity ◽  
B Cell Lymphomas ◽  
Advisory Committees ◽  
Inhibitor Resistance

Mantle cell lymphoma (MCL) and diffuse large B-cell lymphoma (DLBCL) are aggressive hematologic malignancies characterized by the accumulation of lymphoid cells defective in cell apoptosis biology and function. The anti-apoptotic B-cell lymphoma 2 (BCL-2) family proteins are pivotal regulators of the mitochondrial apoptotic pathway and genetic aberrations in these genes are associated with lymphomagenesis and chemotherapeutic resistance. Notably, the anti-apoptotic myeloid cell leukemia 1 (MCL-1) protein is recurrently highly expressed in various kinds of non-Hodgkin's B-cell lymphomas and promotes the survival of lymphoma cells by counteracting pro-apoptotic protein activity. Collectively, these data support the hypothesis that MCL-1 plays a central role in B-cell lymphoma progression and drug resistance. Pharmacologically targeting MCL-1, therefore, represents an attractive strategy to combat these lymphomas. However, previous clinical and pre-clinical data suggest that treatment with single agent anti-BCL-2 family member therapy is associated with rapid acquisition of resistance. To this end, there is a great need to develop and apply selective small molecule MCL-1 inhibitors as part of a first-line therapy or upon emergence of tumor resistance characterized by upregulation of MCL-1 for lymphoma therapy. Here, we exploited the MCL-1 dependency in MCL and DLBCL by implementing pharmacogenomic and chemical proteomic approaches to investigate the molecular drug response and resistance mechanism to MCL-1 inhibitors. In anticipation of the evolution of MCL-1 inhibitor resistance, we modeled MCL-1 inhibitor resistance mechanisms by developing S63845 resistant lines with high doses of S63845 treatment for an extended period in MCL, DLBCL and MCL-derived lines. RNA sequencing and chemical proteomics on paired parental and resistant cells demonstrated that transcriptome and kinome reprograming linked to the MEK and ERK pathways contribute to MCL-1 inhibitor resistance via regulation of the BCL-2 family profile (BCL-2 and BIM), and as such, represent a novel targetable vulnerability in MCL-1 inhibitor resistant lymphoma. Additional analyses revealed synergistic activity of MCL-1 inhibitors (S63845, AZD5991) in combinations with inhibitors of MEK (Trametinib), ERK (SCH772984) and BCR (Ibrutinib) in MCL-1 inhibitor resistant MCL/DLBCL lines and primary samples. These results provide a strong rationale for further evaluation of MCL-1 inhibitor in combination with established therapy in the clinical setting and highlight a potential strategy for overcoming MCL-1 inhibitor resistance. Disclosures Shah: NCCN: Vice-Chair, Acute Lymphoblastic Leukemia Working Group: Membership on an entity's Board of Directors or advisory committees; Kite/Gilead, Precision Biosciences, Novartis, AstraZeneca: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Kite/Gilead, Jazz, Incyte: Research Funding; Moffitt Cancer Center: Current Employment; Kite/Gilead, Celgene/Juno/BMS, Novartis, Pfizer, Amgen, Spectrum/Acrotech, Precision Biosciences, Beigene, AstraZeneca, Pharmacyclics/Jansen, Adaptive: Honoraria. Shain:AbbVie: Research Funding; GlaxoSmithKline: Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Amgen: Speakers Bureau; Sanofi/Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Adaptive: Consultancy, Honoraria; Janssen: Honoraria, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Karyopharm: Research Funding, Speakers Bureau.

scholarly journals Preliminary Clinical Results of a Phase 1 Study Evaluating the Safety and Anti-Tumor Activity of ACTR707 in Combination with Rituximab in Subjects with Relapsed or Refractory CD20+ B-Cell Lymphoma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2966-2966 ◽  
Author(s):  
Ian W. Flinn ◽  
Jonathon B. Cohen ◽  
Luke P. Akard ◽  
Samantha Jaglowski ◽  
Michael Vasconcelles ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Board Of Directors ◽  
Dose Level ◽  
Dose Escalation ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Advisory Committees

Abstract Background: Recent regulatory approvals of two CD19-targeted chimeric antigen receptor (CAR)-expressing autologous T lymphocyte therapies provide compelling evidence of the clinical potential of re-engineering T cells to specifically attack tumor cells, but the broader applicability of these therapies is constrained by safety considerations and target specificity. A universal approach to T cell therapy that enables flexibility in tumor target selection has been demonstrated by engineering autologous T cells to express an antibody-coupled T cell receptor (ACTR) composed of the ectodomain of the CD16 Fc receptor fused to costimulatory and CD3ζ signaling domains. Thus, the ACTR platform couples T cell anti-tumor effector functions, including cytotoxicity, cytokine production, and T cell proliferation, to target-specific therapeutic antibodies. Here we present the preliminary clinical findings of the ongoing, multicenter Phase 1 study, ATTCK-20-03 (NCT03189836), of ACTR707, a CD28-containing ACTR chimeric receptor, in combination with rituximab in subjects with relapsed or refractory CD20+ B cell lymphoma. Methods: The primary objectives of this first-in-human, dose escalation study are to evaluate the safety of the combination of ACTR707 and rituximab and to determine a maximum tolerated dose (MTD) and a proposed recommended phase 2 dose (RP2D). Other objectives include evaluation of antitumor activity, and assessment of ACTR T cell persistence, cytokine levels, and rituximab pharmacokinetics. Eligible subjects must have histologically confirmed relapsed or refractory CD20+ non-Hodgkin lymphoma and have received prior anti-CD20 mAb in combination with chemotherapy. Subjects received lymphodepleting chemotherapy (cyclophosphamide 400 mg/m2 and fludarabine 30 mg/m2) for 3 days, followed by rituximab (375 mg/m2) and ACTR707. Additional doses of rituximab were administered, one dose every 3 weeks in the absence of disease progression. The study is separated into 2 sequential phases, a dose escalation and a safety expansion phase. During the dose escalation phase, ACTR707 is being tested at increasing doses in combination with rituximab. Results: Six subjects were enrolled and received ACTR707 at the first dose level in combination with rituximab: 5 diagnosed with diffuse large B cell lymphoma (83%) and one with follicular lymphoma, Grade 3b (17%). Median age was 61 years (range: 57-76), 83% were male, 50% were treated with ≥3 lines of prior therapy, and 67% had no response to or relapse within 6 months from immediate prior therapy. ACTR707 was successfully manufactured for all subjects and demonstrated post-infusion expansion in the peripheral blood. ACTR+ T cells were detectable at Day 28 post-infusion for all subjects tested. No dose-limiting toxicities (DLTs) were observed at the first dose level in 4 DLT-evaluable subjects (2 subjects experienced disease progression during the DLT evaluation period). There were no cytokine release syndrome (CRS) or autoimmune adverse events (AEs), serious or severe (≥Gr3) neurotoxicity AEs, or deaths on treatment. AEs (all grades) reported in >1 subject included neutropenia (n=3), anemia, decreased appetite, febrile neutropenia, and thrombocytopenia (each in 2 subjects); the 2 events of febrile neutropenia were considered serious. Investigator-reported complete responses were observed in 3 of 6 subjects. These complete responses (duration of response range: 47+ to 81+ days) are ongoing as of the data cut-off. Enrollment into the second dose level is ongoing. Conclusions: ACTR707 in combination with rituximab induced complete responses in 3 of 6 subjects with relapsed or refractory aggressive CD20+ B cell lymphoma treated at the first dose level with ACTR707 in combination with rituximab, with no CRS, serious or severe (≥Gr3) neurotoxicity, or AEs leading to treatment discontinuation. ACTR+ T cells were detectable in all subjects and persisted. These results support the continued dose escalation of ACTR707 in combination with rituximab. Updated data, inclusive of preliminary dose level 2 and correlative biomarkers, will be presented. Disclosures Flinn: Verastem: Consultancy, Research Funding; Janssen: Research Funding; Pfizer: Research Funding; Kite: Research Funding; Forty Seven: Research Funding; BeiGene: Research Funding; ArQule: Research Funding; Takeda: Research Funding; TG Therapeutics: Research Funding; Incyte: Research Funding; Forma: Research Funding; Verastem: Research Funding; Novartis: Research Funding; Agios: Research Funding; Seattle Genetics: Research Funding; Trillium: Research Funding; Merck: Research Funding; Calithera: Research Funding; Constellation: Research Funding; Gilead: Research Funding; Genentech: Research Funding; Infinity: Research Funding; Portola: Research Funding; Pharmacyclics: Research Funding; Curis: Research Funding; Celgene: Research Funding. Cohen:BioInvent: Consultancy; Bristol-Myers Squibb: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Research Funding; Infinity Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding. Akard:Gilead: Speakers Bureau; Celgene: Speakers Bureau; Takeda: Speakers Bureau; Novartis: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau. Jaglowski:Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; Kite Pharma: Consultancy, Research Funding; Juno: Consultancy. Vasconcelles:Unum Therapeutics: Employment. Ranger:Unum Therapeutics: Employment. Harris:Unum Therapeutics: Employment. Payumo:Unum Therapeutics: Employment. Motz:Unum Therapeutics: Employment. Bachanova:Gamida Cell: Research Funding; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; GT Biopharma: Research Funding.

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