Dose-limiting Toxicity Period Research Articles

Feasibility and preliminary safety and efficacy of first-in-human intraperitoneal delivery of MCY-M11, anti-human-mesothelin CAR mRNA transfected into peripheral blood mononuclear cells, for ovarian cancer and malignant peritoneal mesothelioma.

3014 Background: MCY-M11 is a mesothelin-targeting chimeric antigen receptor (CAR) therapy made by a non-viral, mRNA-based platform, for rapid ( < 1 day) CAR manufacturing. We are conducting a phase I dose escalation trial in ovarian cancer and malignant peritoneal mesothelioma (MPM) (NCT03608618). Methods: MCY-M11 are fresh, non-expanded, autologous peripheral blood mononuclear cells (PBMCs) transfected by flow electroporation with mRNA encoding a human anti-mesothelin CAR. Following a 3+3 design, patients are treated in dose level (DL) escalating cohorts (DL1 1.0 x 107, DL2 5.0 x 107, DL3 1.0 x 108, DL4 5.0 x 108 cells/dose), in one cycle of weekly x 3 doses, intraperitoneal (ip) without preconditioning chemotherapy. Results: By January 2020, CP-M11-101 study successfully completed DL1 and DL2 without safety concerns. Based on 11 patients treated in DL1, DL2 and DL3, ip infusion of MCY-M11 is safe and well tolerated. No infusion-related adverse events and no dose limiting toxicities (DLTs) have occurred. No neurotoxicity has been observed. Most reported treatment-related adverse events have been Grades 1-2 per NCI CTCAE. One patient in DL3 presented with G2 pericarditis, fever and transient neutropenia clinically assessed as related SAEs, that resolved without further complications. These events were assessed as on-target off-tumor effects and possibly G1 cytokine release syndrome (CRS). Two unrelated SAEs (G2 confusion in a patient in DL2; G3 enterocutaneous fistula in a patient in DL3) were reported. These 2 patients have been replaced as they did not complete the evaluation period (3 weekly infusions and the DLT 43 day follow up). There have been no treatment-related discontinuations or deaths. Three patients in DL2 showed stable disease (SD) by RECIST 1.1 at the end of the DLT period. Of them, 1 completed the study and did not participate in additional follow up, 1 remained in SD 6 months, and 1 remained in SD 2 months. In DL3, 1 patient remains in SD at 2 months, and evaluation is pending for the other 2 patients. Enrollment is ongoing. Conclusions: Feasibility of 1-day manufacturing of MCY-M11 for ip delivery is demonstrated. Treatment has been safe. Initial SD observed in DL2 and DL3 with one-cycle infusions is encouraging and supports exploration of additional strategies such as the addition of preconditioning chemotherapy and multiple cycles to increase efficacy. Clinical trial information: NCT03608618 .

Abstract P2-17-05: Evaluation of safety, pharmacokinetics and pharmacodynamics of proxalutamide (GT0918), a potent androgen receptor (AR) blocker, in patients with metastatic breast cancer (mBC): Phase I dose escalation trial

Abstract Background: Androgen receptor (AR) blocker has become an increased interest in the treatment of BC, in which about 60-80% patients showed AR positive. However, currently no AR blocker has been approved in mBC. GT0918 is a new chemical entity of AR blocker with possible AR down-regulation. This study is an open-label, single-center, dose escalation phase I trial to assess GT0918 in mBC female patients who have progressed after systemic treatments in China. The primary objectives are to identify the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs). The secondary objectives are to assess pharmacokinetics and pharmacodynamics of GT0918 with single and multiple dosage applications. (CTR20170757) Methods: Patients (pts) with historically confirmed mBC who had progressed after either chemotherapy, hormonal or targeted therapy, or could not tolerate currently standard therapies were eligible. With the starting dose at 100 mg of GT0918, the decision of dose escalation in the 3+3 design was based on the safety and tolerability assessments. GT0918 was administered orally once, followed by a 7-day off-treatment period for single dose PK analysis of drug elimination. Then GT0918 oral administration was resumed once daily for 28 consecutive days and multiple dose PK analysis was assessed at the end of first cycle (28 days). The first 28-days on treatment (cycle 1) was defined as DLT period. Pts manifesting an objective response or stable disease and likely to have clinical benefit from continued treatment were continued on GT0918 thereafter until they experienced one of following events of intolerable toxicities, disease progression or withdrew consent. Results: 18 pts were enrolled and treated with GT0918 since 9/6/2017 as defined in protocol at five dose levels: 100 mg (n = 3), 200 mg (n = 4), 300 mg (n = 4), 400 mg (n = 4) and 500 mg (n = 3) (as to 7/2/2019). All pts progressed more than two lines of therapies with 83.3% (15/18) pts were treated ≥3rd lines. Out of 6 confirmed AR positive pts, two (33.3%) at 300 mg cohort had finished 17 and 19 cycles individually and continue treatment (as 7/2/19). No DLT was observed and MTD has not been reached. GT0918 related adverse events (AEs) were grade 1 or 2 as per CTCAE v4.03, including fatigue, hypertriglyceridemia, anemia, hypercholesterolemia, increased LDL, nausea, loss of appetite, increased ALT, increase of weight loss, constipation and thrombocytopenia. PK profile analysis showed that in the single-dose study, GT0918 showed a fast absorption profile. In the multiple-dose study, the steady-state serum concentration level of GT0918 and its main metabolite were attained at 21 days. Conclusions: Proxalutamide (GT0918) administrated orally once a day is well tolerated in late-stage pts. No DLT has occurred at maximum dose 500 mg. Pts with AR positive biomarker could have better clinical outcomes with GT0918 treatment. GT0918 and its main metabolite exhibited a nonlinear pharmacokinetic profile over the dose range from 100mg to 500 mg. An expanded/phase Ib in AR positive mBC pts has launched in China to evaluate the anti-tumor activity and safety of GT0918. 200 mg and 300 mg were selected for dose expansion. Citation Format: Huiping Li, Ran Ran, Guohong Song, Hanfang Jiang, Ruyan Zhang, Yaxin Liu, Luping Meng, Phoebe Zhang, Ke Chen, Qiaoxia Zhou, Karl Zhou, Youzhi Tong. Evaluation of safety, pharmacokinetics and pharmacodynamics of proxalutamide (GT0918), a potent androgen receptor (AR) blocker, in patients with metastatic breast cancer (mBC): Phase I dose escalation trial [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-17-05.

1032P - Phase I study of low dose whole abdominal radiation therapy (LDWART) in combination with weekly paclitaxel (wP) for platinum resistant ovarian cancer (PROC)

BackgroundHyper-radiation sensitivity is enhanced in cells with mutant p53, which is ubiquitous in high grade serous ovarian cancer (HGSOC). Preclinical data suggests LDWART is a “chemosensitizer” and enhances paclitaxel cytotoxicity. We evaluated the safety and activity of LDWART concurrent with wP (LDWART+wP) in PROC. MethodsPatients (pts) with PROC (progressive disease (PD) < 6 mth from last platinum therapy) were enrolled in a 3+3 dose de-escalation (part A) design, combining wP concurrent with fixed dose LDWART in 60 cGy fractions (twice daily on D1-2 of each week of wP), for 6 continuous weeks. Planned dose levels of wP were 80mg/m2, 70mg/m2, 60mg/m2. After 6 weeks of LDWART+wP, pts received wP chemotherapy alone until PD. Dose expansion (part B) with up to 10 HGSOC pts at maximum tolerated dose (MTD) of LDWART+wP, proceeded to confirm toxicity and activity. ResultsAs of 30/4/2019, 10 pts were enrolled (3 part A, 7 part B). All part B pts had HGSOC. Median lines of prior therapy was 5 (range 1-8), including prior wP in 70%, and prior bevacizumab (bev) in 50% of pts. There was no dose-limiting toxicity (DLT) at wP 80mg/m2 (DLT period = 1st 3 weeks of LDWART+wP), which was deemed the MTD. 6/10 pts completed 6 weeks of LDWART+wP. Discontinuations were due to PD (3/10) or pt withdrawal (1/10). Common related all-grade adverse events (AEs) were nausea (60%), neutropenia (60%), fatigue (60%), neuropathy (40%), diarrhea (30%); common related grade ≥3 AEs were neutropenia (50%) and anemia (20%). Median progression free survival was 3.2 mth and overall survival was 13.5 mth. 9 pts were evaluable for response. 44.4% (4/9) of pts achieved biochemical response, defined as CA125 decrease >50% from baseline, 2/4 were confirmed. 1pt had partial response (PR) despite PD on prior wP, and 5 pts had stable disease (SD), giving an overall response rate of 11.1% (1/9) and disease control rate (PR + SD>6 weeks) of 66.7% (6/9). 3 pts had durable disease control, and completed 12, 18 and 21 weeks of wP respectively. ConclusionsLDWART+wP (80mg/m2) for 6 weeks was safe and tolerable. Encouraging efficacy was seen in this heavily pre-treated population and LDWART+wP may be useful in the context of PROC where bev is contraindicated. Clinical trial identificationNCT02545010. Legal entity responsible for the studyThe authors. FundingRIE2015 National Medical Research Council, National University Cancer Institute Singapore (NCIS) Centre Grant – NCIS Seed Funding. DisclosureD.S. Tan: Honoraria (self): Roche; Honoraria (self), Research grant / Funding (self): Bayer; Honoraria (self): MSD; Honoraria (self): Genmab; Honoraria (self), Research grant / Funding (self): AstraZeneca; Honoraria (self): Merck Serono; Honoraria (self): Tessa Therapeutics; Honoraria (self): Novartis; Research grant / Funding (self): Karyopharm. All other authors have declared no conflicts of interest.

Abstract LB-294: Targeting glutamine addiction of PIK3CA mutant colorectal cancers: From preclinical models to clinical trials

Abstract Glutamine addiction is a major metabolic reprogramming event that occurs in cancer cells. Many tumors exhibit oncogene-dependent addiction to glutamine. As a metabolite, glutamine is first converted to glutamate by glutaminase (GLS) and then to α-ketoglutarate (α-KG) by either a transaminase or a glutamate dehydrogenase. PIK3CA, which encodes the p110α catalytic subunit of phosphatidylinositol 3-kinase α, is frequently mutated in human cancers including 20 to 30% of colorectal cancer (CRC). We found that oncogenic PIK3CA mutations render CRCs addicted to glutamine through an upregulation of glutamate pyruvate transaminase 2 (GPT2), thereby facilitating conversion of glutamate to α-KG. Here, we report that CB-839, a potent GLS inhibitor developed by Calithera Biosciences, inhibits xenograft tumor growth of PIK3CA mutant, but not WT, colorectal cancers. Remarkably, combination of CB-839 with 5-fluorouracil (5-FU) induces regression of xenograft tumors in four different PIK3CA mutant CRC models. These exciting preclinical data prompted us to perform a Phase I and Phase II clinical trial to assess combination of CB-839 with capecitabine, an oral prodrug of 5-FU. For the Phase I trial, patients with advanced solid tumors and disease progression on standard treatment, or for whom capecitabine is an acceptable treatment option, were enrolled. A standard 3+3 design was used to assess escalating doses of CB-839 (400-800 mg) and capecitabine (500-1000 mg/m2) in four dose levels. CB-839 was given orally twice daily continuously and capecitabine was given orally twice daily on days 14/21 of a 21 day treatment cycle. Dose-limiting toxicity period was 21 days. Restaging CT scans were obtained every 9 weeks with response assessment per RECIST. Adverse events were assessed per CTCAEv4. Sixteen patients were enrolled with 7 patients being treated at the final dose level (CB-839 800 mg and Capecitabine 1000 mg/m2). No dose-limiting toxicity were observed. Ten patients achieved stable disease as their best response with 9 being fluoropyrimidine resistant. Among the 16 patients, 12 were CRC patients who were 5-FU resistant. Consistent with our preclinical data, the median progress-free survival (PFS) of seven PIK3CA mutant CRC patients was 25 weeks, whereas the median PFS of five PIK3CA WT CRC patients was 16 weeks. Notably, the PFS of three PIK3CA mutant CRC patients was over six months (8, 9 and 13 months respectively). A Phase II trial of the drug combination in metastatic PIK3CA mutant CRC patients is ongoing. In summary, our preclinical and clinical studies suggest that targeting glutamine metabolism may be a promising approach to treat CRCs with PIK3CA mutations. Citation Format: Yiqing Zhao, Jennifer Eads, David Bajor, zhenghe wang. Targeting glutamine addiction of PIK3CA mutant colorectal cancers: From preclinical models to clinical trials [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-294.

Abstract LB-021: Intratumoral RNA-based TLR-7/-8 and RIG-I agonist CV8102 alone and in combination with anti-PD-1 in a Phase I dose-escalation and expansion trial in patients with advanced solid tumors

Abstract CV8102 comprises a single-stranded non-coding RNA complexed with a cationic peptide. It acts as an agonist to TLR-7/-8 and RIG-I (Ziegler 2018) to stimulate the innate and adaptive immune system. CV8102 was shown to induce an upregulation of inflammatory cytokines, chemokines and IFN-γ related genes at the injection site along with an activation of T, NK, NKT and migratory dendritic cells in the draining lymph nodes (Heidenreich 2015). Intratumoral (IT) CV8102 demonstrated dose-dependent anti-tumor activity and synergized with systemic PD-1 inhibition in preclinical models. Methods This Phase I study investigates IT CV8102 as single agent and in combination with systemic anti-PD-1 antibodies (as per product label). Patients (pts) with advanced inoperable melanoma (MEL), cutaneous/head and neck squamous cell or adenoid cystic carcinoma (cSCC, SCCHN, ACC) are eligible for single agent CV8102, pts with MEL and SCCHN who did not respond or slowly progressed on anti-PD-1 therapy are eligible for the combination. CV8102 is administered for up to 8 IT injections into a single accessible tumor lesion over a 12-week period. A Bayesian logistic regression model with overdose control is used for the dose escalation parts. Response is assessed by RECIST 1.1/irRECIST (injected and non-injected target lesions). Pre- and on-treatment samples are collected for biomarker analyses. Results A total of 20 pts have been treated with either CV8102 alone (N=15: 6 MEL, 2 SCCHN, 5 ACC, 2 cSCC) or CV8102 in combination with anti-PD-1 (N=5: 4 MEL, 1 SCCHN). Dose cohorts with doses up to 150 µg (CV8102 alone) and 100µg (CV8102+anti-PD-1) have been completed. Most common AEs were mild to moderate flu-like symptoms and injection site reactions. No dose limiting toxicities (DLT) were observed during the DLT period of the first two weeks of treatment. 12 pts treated with CV8102 alone were evaluable for response assessment. 1 MEL pt treated at 150µg experienced a complete regression of injected and non-injected lesions. This patient also experienced a marked increase of IL-6 and CRP at 6 and 24 hours after the first injection, respectively. 7 pts achieved stable disease, with two pts treated at 100 µg (SCCHN pt) and 200µg (MEL pt who had developed acquired resistance to previous anti-PD-1 therapy) showing regression of non-injected lymph node lesions. Dose escalation parts are continuing, updated safety and efficacy results will be presented. Conclusion Intratumoral single agent CV8102 appears well tolerated and showed preliminary evidence of clinical efficacy with shrinkage of injected and non-injected lesions. Citation Format: Thomas Eigentler, Juergen Krauss, Jutta Schreiber, Carsten Weishaupt, Patrick Terheyden, Lucie Heinzerling, Peter Mohr, Benjamin Weide, Ralf Gutzmer, Juergen C. Becker, Felix Kiecker, Angelika Daehling, Fatma Funkner, Regina Heidenreich, Sarah-Katharina Kays, Ute Klinkhardt, Birgit Scheel, Oliver Schoenborn-Kellenberger, Tobias Seibel, Claudia Stosnach, Tanja Strack, Ulrike Gnad-Vogt. Intratumoral RNA-based TLR-7/-8 and RIG-I agonist CV8102 alone and in combination with anti-PD-1 in a Phase I dose-escalation and expansion trial in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-021.

A phase I/II study of proxalutamide (GT0918), a potent androgen receptor blocker, in patients with mCRPC progressed after both hormonal therapy and chemotherapy.

169 Background: GT0918 is a new chemical entity of androgen receptor (AR) blocker. A phase I/II study was conducted to identify dose-limiting toxicities (DLTs) and to assess safety, tolerability, and PK of GT0918 in pts with mCRPC who have progressed on standard of care (SoC) and experimental therapies in the United States. Methods: Patients (pts) with histologically confirmed mCRPC who had progressed after both hormonal therapy (abiraterone or/and enzalutamide) and chemotherapy (e.g., docetaxel) were eligible. GT0918 was administered once daily orally for 28 consecutive days, followed by a 7-day off-treatment period for PK analysis. The first 28-days on treatment (cycle 1) was defined as DLT period. Pts continued on receiving GT0918 thereafter until they experienced one of following events of intolerable toxicities, disease progression or withdrew consent. Results: 35 pts were enrolled to GT0918-US-1001 trial with 6 dose escalations of study drug defined in protocol: 50 mg (n = 3), 100 mg (n = 6), 200 mg (n = 6), 300 mg (n = 7), 400 mg (n = 7) and 500 mg (n = 6). All pts progressed on multiple lines of therapies including but limited to bicalutamide, abiraterone, enzalutamide, docetaxel, cabazitaxel, radium 223, sipuleucel T and pembrolizumab. No DLT was observed and MTD has not been reached. GT0918 related adverse events (AEs) were less than 10% and grade 1 or 2 as per CTCAE v4.03, including fatigue, nausea, dizziness, loss of appetite, back pain, hot flush, hypercholesterolemia, anemia, constipation, etc. Two events of grade 3 fatigue and one event of grade 4 elevated creatine kinase (CK) were reported. Stable disease by imaging scans at 24 weeks by dose group were; 1/50 mg, 1/100mg, and 4/400mg. Three pts on 500mg finished 3 cycles and continue on the treatment (as 10/15/18). PSA decreases were also seen among pts at 500mg dose level for 4 cycles. Conclusions: GT0918 administrated orally once a day is well tolerated and resulted in SD in late-stage pts. No DLT has occurred to date (at 500 mg) and dose escalation is planned to 600 mg or higher. Extended/Ph II trial will further evaluate safety and efficacy of GT0918 in mCRPC pts. Clinical trial information: NCT02826772.

Updated Phase 1 Results of Zuma-3: Kte-X19, an Anti-CD19 Chimeric Antigen Receptor T Cell Therapy, in Adult Patients with Relapsed/Refractory Acute Lymphoblastic Leukemia

Background Although ∼1/2 of adult patients (pts) with acute lymphoblastic leukemia (ALL) achieve long-term survival, those who relapse have poor long-term outcomes. The initial report of Phase (P) 1 of ZUMA-3, the P1/2 trial of KTE-X19 for treatment of relapsed/refractory (R/R) ALL (NCT02614066), demonstrated a 71% complete remission (CR) rate (CR or CR with incomplete hematologic recovery [CRi]), 88% undetectable minimal residual disease (MRD), and manageable toxicity (Shah et al. ASH 2017. #888). Here, we present updated ZUMA-3 P1 safety and efficacy data. Methods Adult pts (≥ 18 y) with R/R ALL (Ph+ allowed), > 5% bone marrow (BM) blasts, and ECOG 0-1 received 2, 1, or 0.5 × 106 CAR T cells/kg after low-dose conditioning chemotherapy. The primary endpoint for P1 was incidence of dose-limiting toxicities (DLTs). Key secondary endpoints included incidence and time to onset and resolution of adverse events (AEs), rate of undetectable MRD remission in the BM, and duration of remission. Safety analyses included all pts who received KTE-X19; pts with ≥ 2 months of follow-up were evaluated for efficacy. Results As of April 12, 2018, 35 pts have received KTE-X19 (median follow-up of 11 months [range, 2 −25 months]). Median age was 40 years (range, 18 – 69 years), 51% male, 66% ECOG 1, 37% prior blinatumomab, and 60% ≥ 3 prior lines of treatment. Median BM blast burden at Screening was 70% (range, 5 −100). Six, 14, and 15 pts received 2, 1, and 0.5 × 106 cells/kg doses, respectively. No DLTs were observed in the DLT period. The most common Grade ≥ 3 AEs were hypotension (40%) pyrexia (34%), decreased platelet counts (34%), and anemia (31%). Grade ≥ 3 cytokine release syndrome (CRS) occurred in 9 pts (26%, median time to onset 5 days [range, 1 −15 days]); events resolved in all pts (excluding 2 with a Grade 5 event), and the median time to resolution was 11 days (range, 7 −42 days). There were 2 KTE-X19-related Grade 5 events: 1 cerebral infarction at the 0.5 × 106 cells/kg dose and 1 previously reported multiorgan failure secondary to CRS at the 2 × 106 cells/kg dose. Grade ≥ 3 neurologic events occurred in 16 pts (46%, median time to onset 7 days [range, 4 −24 days]); neurologic events resolved in all pts (excluding 2 patients with unresolved events at death), with a median time to resolution of 17 days (range, 6 −53 days). Among the 32 pts evaluable for response, the overall rate of undetectable MRD was 78% (95% CI, 60%–91%).CR or CRi was achieved by 23 pts (72%), and 1 pt (3%) had blast-free BM. Conclusion High remission rates were achieved by adult pts with R/R ALL, with ∼3/4 of pts achieving CR or CRi with undetectable MRD after a single dose of KTE-X19 in ZUMA-3. The safety profile was generally manageable, and most cases of high-grade CRS and neurologic events resolved. These results demonstrate that KTE-X19 offers clinical benefit for pts with otherwise limited treatment options.

Delayed immune-related adverse events in assessment for dose-limiting toxicity in early phase immunotherapy trials

BackgroundImmunotherapy (IO) agents can cause late-onset immune-related adverse events (irAEs). In phase I trials, observation for dose-limiting toxicities (DLTs) is typically limited to the first cycle. The incidence of delayed-onset DLTs and their potential impact on dose determination have not been fully elucidated. Patients and methodsConsecutive patients enrolled in early phase IO trials at Princess Margaret Cancer Centre between August 2012 and September 2016 were retrospectively reviewed, applying trial-specific definitions for DLTs. A clinically significant AE (csAE) was defined as a treatment-related adverse event requiring corticosteroids, hormone replacement, IO delay or discontinuation. ResultsA total of 352 consecutive trial enrolments in 21 early phase clinical trials were included. Two-hundred seventy-eight patients (79%) received monotherapy and 74 (21%) received combination IO. Two hundred sixty (74%) patients experienced irAEs. There were two protocol-defined DLTs. Twenty (5.7%) patients had 24 csAEs qualifying as DLTs except for occurrence after the protocol-specified DLT period. One-hundred and six (10%) of irAEs were csAEs, including endocrine (26%), respiratory (14%), gastrointestinal (11%), general (10%), dermatological (8%), hepatic (8%), musculoskeletal (6%), pancreatic (6%), haematological, metabolic, neurological, cardiac (each 2%), infective and ocular (each 1%) events. The highest risk of first-onset csAE was during the first 4 weeks compared with the period from 4 weeks to end of treatment (odds ratio 3.13, 95% confidence interval 1.95–5.02). The median time to first onset csAE was significantly shorter with combination than monotherapy IO (32 vs. 146 days, P < 0.001). ConclusionsIn our series of early phase IO trials, the risk of csAE was highest during the initial 4 weeks on IO treatment, supporting the use of the conventional DLT period for dose escalation decision. However, there were 24 clinically significant late-onset DLTs in 5.7% of patients. Combination IO was associated with greater risk of and also earlier onset for csAE, which may need to be considered for early phase trial design.

Outcomes of Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma Included in Phase I Clinical Trials

INTRODUCTIONThe phase 1 selection for clinical trials of patients with relapsed or refractory Diffuse Large-B cell lymphoma (R/R DLBCL) with a potentially rapid tumor growth is a challenge. Prognostics' factors identification could help to better orient patients in appropriate clinical trials. This study is focused on DLBCL to evaluate their outcomes in phase I clinical trials. Our main objectives were to identify prognostic factors, attest the investigational drugs' safety and perform a preliminary assessment of drugs' efficacy.METHODAll consecutive patients with R/R DLBCL included in phase I clinical trial at a single cancer center in France between 2008 and 2017. If a given patient had participated in several phase I clinical trial, only the data from his first trial were examined. The patients' and DLBCL characteristics, the safety data and the efficacy outcomes were recorded. Reponses were assessed according to the International Harmonization Project in Lymphoma Cheson 2007 criteria. Overall responses rates (ORR) included partial responses (PR) and complete response (CR) and tumor control rates included overall responses and stable disease (SD).RESULTSA total of 101 patients (males: 63,4%) with R/R DLBCL were included in a panel of 21 clinical trials. The median age was 64 (range 21-86). Before their inclusion in a phase I trial, patients had received a median of 3 (1-7) lines of treatment and 25,7% of patients had undergone an autologous stem cell transplantation. At the cute-off date, 5 of the 101 patients (4,95%) were still taking the investigational drug. The median progression-free survival and overall survival (OS) were 1,8 and 9,7 months. High-grade toxicity (grade 3 or higher) occurred in 47 of the 101 patients (46,5%), and was related to the investigational drug in 29 of these cases (61,7%). The most important drugs-related toxicity was a hematological toxicity (neutropenia and thrombocytopenia) for 79,3% of patients, other toxicities were digestive toxicity (5,9%), cutaneous toxicity (2,9%), hepatotoxicity (2,9%) and pneumopathy (2,9%). Dose-limiting toxicity (DLT) was experienced by 7 (6,9%) of the 101 patients. The time from D1C1 (day 1, cycle 1) to the occurrence of high-grade toxicity was 1,2 months (range 0,2-9,5). High-grade toxicity occurred during the DLT period (< 6 weeks) for 27 of the 46 patients (58,7%) and after the DLT period in the remaining 19 (41,3%) patients.Factors associated with poor overall survival (overall survival inferior to the median OS) were Ann Arbor staging (73.6% of poor OS patients (< 9.7 months) with a performance status at 4), serum albumin (30.2% of poor OS patients with a low rate of serum albumin ≤ 35 g/L), serum LDH (79.2% of poor OS patients with a high rate of serum LDH > 250 U/L) and progressive disease (90.6% of poor OS patients had a trial withdrawal because of progression). The overall objective response and disease control rates were 25% and 43%. The median trial duration was 1.9 months and were respectively 12,1 and 5,5 months for responders (PR and CR) and controlled patients (PR and CR and SD). 36.6% of patients were prematurely withdrawing of study (before weeks 6). Factors associated with premature withdrew were performance status at baseline (67.6% of early withdrawal patients at performance status 1); Ann Arbor staging (67.6% of early withdrawal patients at Ann Arbor stage 4); serum LDH (73% of early withdrawal patients with a high rate of serum LDH > 250 U/L) and serum albumin (35,1% of early withdrawal patients with a low rate of serum albumin ≤ 35 g/L).CONCLUSIONHigh-grade toxicity occurred after the DLT period in 41.3% of patients with R/R DLBCL, suggesting that the conventional concept of dose-limiting toxicity should be redefined in the era of modern cancer therapies. Besides, even if the phase 1 selection for clinical trials is very selective, it's necessary to better orient patients in hematology. In fact, 36.6% of patients were prematurely withdrawing of study which could be anticipated thanks to the identification of prognostics' factors. Although the objective response is only a secondary endpoint in phase I clinical trials, the median duration of participation in trials (almost one year for responders and 5.5 months for controlled patients) are relevant for some new possibilities of therapeutics in the field of early drugs clinical trials. [Display omitted] DisclosuresRibrag:NanoString Technologies: Consultancy, Honoraria; epizyme: Consultancy, Honoraria; Incyte Corporation: Consultancy; MSD: Honoraria; Roche: Honoraria, Other: travel; Infinity: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Other: travel; Amgen: Research Funding; Servier: Consultancy, Honoraria; pharmamar: Other: travel; Gilead: Consultancy, Honoraria; argenX: Research Funding.

Results from a Phase Ib Evaluation of Tazemetostat (EPZ-6438) in Combination with R-CHOP in Poor Prognosis Newly Diagnosed Diffuse Large B Cell Lymphoma (DLBCL): a Lysa Study

Results from a Phase Ib Evaluation of Tazemetostat (EPZ-6438) in Combination with R-CHOP in Poor Prognosis Newly Diagnosed Diffuse Large B Cell Lymphoma (DLBCL): a Lysa Study

A Phase 1b Study Investigating the Combination of the Tetravalent Bispecific NK Cell Engager AFM13 and Pembrolizumab in Patients with Relapsed/Refractory Hodgkin Lymphoma after Brentuximab Vedotin Failure: Updated Safety and Efficacy Data

A Phase 1b Study Investigating the Combination of the Tetravalent Bispecific NK Cell Engager AFM13 and Pembrolizumab in Patients with Relapsed/Refractory Hodgkin Lymphoma after Brentuximab Vedotin Failure: Updated Safety and Efficacy Data

Updated Phase 1 Results of Zuma-3: Kte-C19, an Anti-CD19 Chimeric Antigen Receptor T Cell Therapy, in Adult Patients with Relapsed/Refractory Acute Lymphoblastic Leukemia

Updated Phase 1 Results of Zuma-3: Kte-C19, an Anti-CD19 Chimeric Antigen Receptor T Cell Therapy, in Adult Patients with Relapsed/Refractory Acute Lymphoblastic Leukemia

Phase I Study of the Antibody-Drug Conjugate Brentuximab Vedotin Combined with Re-Induction Chemotherapy in Patients with CD30-Expressing Relapsed/Refractory Acute Myeloid Leukemia

Background: Brentuximab vedotin (BV) is an antibody-drug conjugate (ADC) consisting of an antibody specific for human CD30, an anti-microtubule agent monomethyl auristatin E (MMAE), and a protease-cleavable linker attaching MMAE to the antibody. BV is efficacious therapy against certain CD30-expressing malignancies, including classical Hodgkin lymphoma and anaplastic large cell lymphoma, and is currently approved for use in these diseases. We and others previously demonstrated CD30 expression on a sizeable proportion of primary AML samples as well as cell lines. Given this data, we conducted a phase I dose-escalation trial of BV in combination with re-induction chemotherapy (MEC) for patients with relapsed or refractory AML.Methods: In this phase I, 3+3 cohort dose-escalation study, BV was administered 3 days prior to initiation of MEC re-induction for relapsed or refractory AML. Eligibility for enrollment included adults over age 18, adequate organ function, an ECOG performance status of ≤ 2, and a diagnosis of relapsed or refractory AML with > 20% CD30 expression (as assessed by immunohistochemistry or flow cytometric analysis). On day 1 of the trial, all enrolled participants were initiated on therapy with BV intravenously using three sequential dosing levels (0.9 mg/kg, 1.2 mg/kg, 1.8mg/kg). On day 3, patients were initiated on MEC re-induction chemotherapy (Mitoxantrone 10mg/m2 IV administration for five days [D3-8], etoposide 100mg/m2 IV D3-8, cytarabine 1000mg/m2 IV D3-8). The period of dose limiting toxicity (DLT) assessment occurred during the period of re-induction (approximately D1-35). Once dose escalation for BV reached a dose of 1.8 mg/kg IV, no further escalation would occur. An additional cohort of ten patients were to be treated at this maximum dose, or if a maximum tolerated dose (MTD) was reached, an additional 10 patients were to be treated at this dose. Thereafter, maintenance therapy with BV could be initiated, and administered IV every 21 days, as per dose level during prior re-induction, and continued for up to 12 months. Those eligible for stem cell transplant (SCT) were removed from study for this purpose.Results: 22 eligible patients were enrolled on study. The median age was 58 (range 23-72); 15 (68%) were male, and 20 (91%) were Caucasian. 7 patients (32%) had secondary AML (6 with antecedent MDS and 1 with therapy related AML). 6 (27%) exhibited adverse risk karyotype. FLT3 mutations were seen in 7 (32%), NPM1 in 4 (18%), and CEBPA in 2 (9%). The median degree of blast CD30 expression in those assessed by flow cytometry was 92% (range 30-98%). 6 patients had refractory disease, while the remaining had relapsed AML at time of enrollment. 10 patients (46%) had undergone prior allogeneic stem cell transplantation (SCT), one of whom had undergone two prior stem cell transplants. Three patients were treated at dose level 1, 5 at dose level 2, and 4 at dose level 3. Two of the patients treated at dose level 2 were removed prior to end of DLT period due to lack of response and were replaced, and 1 patient treated at dose level 3 died due to infectious complications prior to end of DLT monitoring period and was replaced. No new attributable toxicities apart from that expected from MEC re-induction alone were seen with the combination therapy. No DLTs were detected, and the recommended phase 2 dose (RP2D) was deemed to be dose level 3 (1.8 mg/kg). An additional 10 patients were treated at the RP2D. Overall, 4 patients achieved a complete remission (CR) and 4 achieved a complete remission with incomplete hematologic recovery (CRi), for a composite remission rate (CCR) of 36% (8/22). Among the 14 patients treated at the RP2D of 1.8mg/kg, 6 achieved a CR or CRi (CCR 43%). Of the remaining cases, one was replaced prior to response assessment and the others experienced progressive disease. The degree of baseline CD30 expression by flow cytometry did not appear to predict for response in this phase 1 dose escalation study, although study of correlative samples is ongoing.Conclusions: BV is well tolerated when administered in conjunction with conventional re-induction chemotherapy in patients with relapsed-refractory AML, in whom CD30 is an intriguing target. Adverse events on this study were predominantly expected and related to marrow suppression from MEC re-induction. No DLT was identified. Additional and larger studies are needed to more comprehensively assess the efficacy of CD30-targeted therapy in AML. DisclosuresFathi:Jazz: Honoraria; Boston Biomedical: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Astellas: Honoraria; Agios: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria. Emadi:NewLink Genetics: Research Funding. Brunner:Takeda: Research Funding; Novartis: Research Funding; Celgene: Consultancy, Research Funding. Amrein:Takeda: Research Funding.

Efficacy of Lenalidomide and Bortezomib for Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS) Relapsing after Allogeneic Stem Cell Transplantation

Introduction: AML and MDS are advanced myeloid malignancies more common among older adults and generally associated with poor outcomes. Allogeneic hematopoietic cell transplantation (HCT) may cure a proportion of affected patients, but disease relapse remains common and is associated with dismal survival. High doses of lenalidomide may modulate graft-vs-leukemia (GvL) effects, and have shown encouraging responses for relapsed AML. Bortezomib may also augment GvL and potentiate the effect of other chemotherapeutics. We conducted a phase I study of escalating doses of bortezomib added to high-dose lenalidomide in patients with AML and MDS, who had relapsed following HCT.Methods: We enrolled patients aged ≥ 18 years, with AML or MDS, relapsing after HCT in a ‘3+3‘ dose-escalation study. Patients with grade ≥3 GVHD, or chronic GVHD requiring >20mg/d of prednisone were excluded. Patients otherwise had to be off immunosuppressive therapy for 2 weeks. Lenalidomide 50mg/d was administered on days 1-21 of 28-day induction cycles. On days 2, 5, 9, and 12, subcutaneous bortezomib was administered at escalating dose levels: 0.7mg/m2, 1.0mg/m2, and 1.3mg/m2. Patients could receive up to two cycles of induction. After reaching the maximally tolerated dose (MTD), 9 patients were enrolled at the recommended phase II dose (RP2D) of bortezomib 1.3mg/m2.Dose limiting toxicities (DLTs) included G4 peripheral neuropathy, G3+ aGVHD, moderate/severe cGVHD, non-resolving G3/4 non-hematologic toxicities, and the inability to receive at least 50% of both drugs during induction. The DLT period spanned up to 2 induction cycles, but could be 1 cycle if a patient entered complete remission (CR) or complete remission with incomplete count recovery (CRi) after the first cycle. Response to induction was the best response after up to two cycles of induction and was assessed in those patients treated at the MTD/RP2D. Donor lymphocyte infusions (DLI) were allowed after induction per the treating physician.Results: A total of 21 patients were enrolled, with a median age of 66 years at study entry (range 23-74). The patients were predominately male (62%) and white (86%), while 2 patients (10%) identified as of Hispanic ethnicity. The majority had AML (19/21), with 10 of the AML patients having disease arising from prior CMML (1), MDS (7), or MPN (2). Three patients had del(5q); 2 patients had loss of 17p and 2 patients had complex cytogenetics. Three patients were enrolled at bortezomib dose levels of 0.7mg/m2 and 1.0mg/m2; at dose level 3, one patient experienced a DLT for receiving < 50% of doses and the cohort was expanded to 6 total patients. An additional 9 expansion patients were then treated at this dose level for a total of 15 patients treated with lenalidomide 50mg and bortezomib 1.3mg/m2. During dose expansion, grade 4 toxicities attributed to study drug included grade 4 neutropenia (n=5), thrombocytopenia (n=3), and febrile neutropenia (n=1), consistent with what was seen during dose escalation. Across all cohorts (n=21), 4 patients achieved CR/CRi.Of the 15 patients treated at the MTD/RP2D, 4 patients had progressive disease after the first induction cycle, and 2 patients stopped therapy during induction cycle 2. A total of 9 patients completed both induction cycles. Of the 15 patients treated at the RP2D, 3 achieved a CR/CRi (20%, 90%CI 5.7-44.0%). Another 2 patients had stable disease. One additional patient achieved a CR in the first dose cohort (Figure 1). Chimerism during treatment tracked with disease response; one patient with persistent low chimerism achieved CRi and received DLI as well (patient 3, who also harbored a TP53 mutation). A total of 3/13 patients tested harbored TP53 mutations; 2/3 achieved CRi while the third (patient 2) came off treatment during induction.Conclusions: Lenalidomide may be safely combined with bortezomib in patients with AML and MDS relapsing after HCT, with an encouraging rate of complete remission (20%) in this poor risk population. Overall toxicities with this regimen were manageable, and largely related to cytopenias. Of note, 2 of the 4 CR/CRi responses on the trial were in patients with TP53-mutated disease, suggesting that this regimen should be further evaluated in this high-risk population, and combination with donor lymphocyte infusion may also merit investigation in larger studies. DisclosuresBrunner:Takeda: Research Funding; Celgene: Consultancy, Research Funding; Novartis: Research Funding. Rosenblatt:Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Celgene: Research Funding. Amrein:Takeda: Research Funding. Chen:Magenta Therapeutics: Consultancy; REGiMMUNE: Consultancy; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda Pharmaceuticals: Consultancy. Fathi:Jazz: Honoraria; Seattle Genetics: Consultancy, Honoraria; Astellas: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Boston Biomedical: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Agios: Honoraria, Research Funding.

A phase I/II study of pembrolizumab (P) with gemcitabine (G) in patients (Pts) with previously-treated advanced non-small cell lung cancer (NSCLC): Phase I safety results.

e20605 Background: P, an anti-PD1 antibody active in advanced NSCLC, has optimal benefit in tumors with high PD-L1 expression. G may increase antigen cross-presentation and prime CD8 T cell responses via increased tumor cell apoptosis. The combination of antigen cross-presentation and T cell activation may have a synergistic effect with concurrent anti-PD1 immunotherapy. This study is evaluating P + G in pts with previously-treated advanced NSCLC with goal to establish feasible dosing prior to phase II evaluation. Methods: The phase I portion enrolled sequential cohorts of 2 pts each with advanced NSCLC (1-3 prior lines of therapy), regardless of PD-L1 status. Treatment consisted of G, 1250 mg/m2, Days (D) 1 &amp; 8 + P 200 mg D 1; 21-day cycles. Pts received G to max 6 cycles, P to max 2 years. Each cohort closed until pts completed 6 weeks therapy (2 cycles). Dose limiting toxicity (DLT) was defined as Gr 4 hematologic or Gr 3/4 non-hematologic toxicity at least possibly treatment-related within the first 6 weeks. Dose de-escalation would occur if ≥ 2 related DLTs occurred in the first 6 pts (accrual 6-36 pts); de-escalation was allowed for each drug independently based on toxicity attribution. Tumor tissue was collected for central PD-L1 testing and immune score analysis. Exploratory analysis of immune response via protein array and whole blood immunophenotyping is pending. Results: 6 pts were enrolled. Male/Female: 2/4; Age 53-73 (Median 67.5); ECOG 0/1: 1/5 pts, respectively. Median prior lines of therapy: 1 (Range 1-3). DLT: Gr 4 pulmonary hemorrhage with respiratory failure (1 pt, related to G). Other toxicities in DLT period: Gr 3 neutropenia (1), anemia (2 events in 1 pt). Other toxicities were Gr 1/2. 1 pt developed Gr 3 pneumonitis after DLT period ended (after cycle 3) and was removed from study treatment. Median cycles: 4 (Range 2-8). Primary reason for discontinuation was progression (4 pts). PD-L1 results by central analysis are pending. Conclusions: 1 DLT was observed in phase I; de-escalation was not triggered and the combination is considered feasible for phase II evaluation with G 1250 mg/m2 and P 200 mg (enrolling). Clinical trial information: NCT02422381.

A phase I trial of the oral hedgehog inhibitor taladegib (LY2940680) in combination with weekly paclitaxel in patients with advanced, solid tumours.

2594 Background: Aberrant Hedgehog (Hh) signaling is implicated in carcinogenesis and is associated with poor prognosis in multiple tumours types. Hh inhibitors increase sensitivity to paclitaxel in taxane-resistant cell lines. Taladegib is an orally bioavailable, potent inhibitor of Smoothened, a key Hh pathway component, with activity in basal cell carcinoma. The single agent recommended dose is 400mg od. We present the dose escalation phase of a phase I study of weekly paclitaxel with oral taladegib. Methods: Primary objective: determine the dose limiting toxicity (DLT) and maximum tolerated dose (MTD) of taladegib on a continuous oral daily dosing regimen in combination with paclitaxel (80mg/m2, iv, day 1, 8 and 15 q 28) in patients with advanced solid cancers. Secondary objectives: assess the safety and tolerability, determine the recommended phase II dose (RP2D), and evaluate the pharmacokinetics of taladegib and paclitaxel. Exploratory objective: assess preliminary efficacy. A standard 3 + 3 dose escalation design was used. All patients received up to 6 cycles of paclitaxel. In addition, successive cohorts received continuous oral taladegib continued until progression or unacceptable toxicity as follows: dose level 1: 100mg od; 2: 200mg od; 3: 400mg od. Results: No DLTs were seen at dose level 1 or in the first 3 patients at dose level 2. 3 DLTs of grade 2 neuropathy were seen at dose level 3 (400mg taladegib); therefore, dose level 2 was expanded to 6 patients. No DLT was seen in the fourth patient and 2 additional patients have started treatment. After the DLT period 2 patients developed G2 and 4 developed G1 neuropathy. Other non DLT, drug-related G3 toxicities: uncomplicated neutropenia x2, muscle cramp x1 and fatigue x1. To date, 3 patients have had partial responses. Conclusions: The combination of daily oral taladegib and weekly paclitaxel is feasible. DLT of G2 neuropathy was seen at 400mg. Promising activity has been seen in solid tumours. A dose expansion cohort is due to commence in high grade ovarian carcinoma. ISRCTN No:ISRCTN15903698 Eudract Ref:2014-004695-37 Funded by Cancer Research UK C8361/A18775 and Ignyta. Sponsored by NHS Greater Glasgow and Clyde. Clinical trial information: ISRCTN15903698.

AMC-053: Pilot Study of an Oncolytic Viral Strategy Using Bortezomib with ICE +/- Rituximab for Relapsed/Refractory HIV+ Lymphomas

Introduction:Both HIV+ Hodgkin and non-Hodgkin lymphomas have higher rates of latent infection by the gamma-herpesviruses (GHVs), Epstein-Barr virus (EBV) and Kaposi sarcoma-associated herpes virus (KSHV), than corresponding lymphomas in the HIV-seronegative population. Bortezomib, a proteasome inhibitor, induces lytic activation of both EBV and KSHV. Lytic activation of GHVs latently infecting lymphoma cells is hypothesized to beneficial both for direct tumor cell lysis as well as increased cytotoxic immune response due to viral lytic gene products. Furthermore, preclinical studies found proteasome inhibition impairs HIV infectivity via preservation of human anti-retroviral APOBEC3G, suggesting a novel therapeutic strategy to control HIV. Given that therapy of relapsed or refractory HIV-associated lymphoma (R/R-HAL) results in modest rates of remission, we sought to capitalize on the high viral association within HAL using an oncolytic strategy with bortezomib.Objectives:The primary objective of this study was to evaluate safety and overall response rate (ORR) of R/R-HAL to bortezomib combined with ifosfamide, carboplatin, etoposide +/- rituximab (ICE/R).The secondary objectives of this study were to estimate the impact of bortezomib on lytic activation of EBV and KSHV, using peripheral blood mononuclear cell (PBMC) viral loads, and on HIV using single copy plasma viral loads; to report overall survival at 1 year (1yr-OS); and to correlate EBV and KSHV viral load changes with lymphoma response.Methods:A 3+3 dose escalation design with a 7-day lead-in period of bortezomib alone prior to bortezomib + ICE/R allowed for assessment of early effects of bortezomib on viral loads. Bortezomib was given intravenously on day 1 and 8 of each cycle at one of 4 dose levels: 0.7, 1, 1.3 or 1.5 mg/m2. Standard dose ICE +/- R began day 8 of cycle 1 (28-day cycle); ICE +/- R began day 1 of all subsequent cycles (21-day cycle). Rituximab was included in the regimen only for CD20+ lymphoma.Binomial proportions were used to estimate ORR. The product-limit (Kaplan-Meier) method was used to estimate 1yr-OS. The Wilcoxon signed rank test was used to evaluate changes in viral loads.Results:Twenty-three subjects were enrolled from 7 sites within the AIDS Malignancy Consortium (AMC). More than 90% of enrolled subjects were men and half were minorities; at baseline, 20/23 were on antiretroviral therapy, median CD4 count was315/µL and median HIV viral load was undetectable. Mean age was 50 years. Over half of subjects had stage IV HAL; the majority had diffuse large B-cell lymphoma (DLBCL) (n=15), 2 had primary effusion (PEL), 3 had plasmablastic and 2 had Hodgkin lymphoma.Figure 1 summarizes grade 3-4 toxicities of the 22 subjects evaluable for adverse events during the dose-limiting toxicity period (cycles 1+2). The maximum tolerated dose was not reached at the highest dose cohort studied (bortezomib 1.5mg/m2).Responses occurred in 14/22 subjects initiating protocol therapy: 5 complete and 9 partial responses (PR). Of the 20 subjects who completed 2 or more cycles, the ORR was 80%. Nine of the responders underwent auto-hematopoietic stem cell transplant after protocol therapy. 1yr-OS was 55%.After bortezomib alone, median values of EBV PBMC viral load measured on day 8 were 2x greater than baseline. However, paired analysis did not confirm significant change in this small sample (n=16 evaluable), and there was no correlation found between change in EBV viral load and response. The 2 subjects with known KSHV+ lymphoma (PEL) each had more than a 1-log increase in day 8 KSHV viral load compared with baseline. Both of these subjects attained a PR from protocol therapy.Conclusions:Addition of bortezomib to ICE/R in R/R HAL is feasible with ORR (80%) and 1yr-OS (55%) comparing very favorably with a prior AMC retrospective report of ICE/R in R/R HAL (n=31, ORR 32%, 1yr-OS 38%, Bayraktar 2012). Evaluation of data collected from individual subjects suggests GHV lytic activation may occur with bortezomib alone. However, the lower bortezomib dose levels used to treat the bulk of study subjects and the limited study sample size limit our power to confirm this conclusion. We plan to further explore the effects of proteasome inhibition on GHVs. Evaluation of the impact of bortezomib on HIV replication is pending and will be presented at the meeting. [Display omitted] DisclosuresReid:Millennium: Research Funding. Sparano:Takeda: Research Funding.

A Phase I Study of the Multi-Targeted Tyrosine Kinase Inhibitor Cabozantinib in Patients with Acute Myeloid Leukemia

Cabozantinib is a multi-targeted tyrosine kinase inhibitor (TKI) of FLT3, MET, AXL, VEGFR, and KIT, all of which are implicated in the pathogenesis of acute myeloid leukemia (AML). Cabozantinib has been studied in clinical trials of solid tumors, and is FDA approved for use in medullary thyroid and renal cell carcinoma. Despite multiple relevant targets, cabozantinib has not been previously studied in AML. Given up-regulation of these key enzymes and related pathways in AML, we sought to assess the safety and tolerability of cabozantinib in this population.The primary objective of this phase I, 3+3 cohort dose-escalation study was to define the maximum tolerated dose (MTD) of cabozantinib in patients with AML. Eligibility included adults ≥ age 18, with relapsed or refractory (R/R) AML, or those aged ≥ 70, with new diagnosed AML but ineligible for or declining conventional therapy. Study treatment required a white blood cell count (WBC) of < 30,000/mm3, but concurrent treatment with hydroxyurea was allowed to control WBC during the first 15 days of cycle 1. The first dose level was 40MG by mouth daily (QD), a dose previously demonstrated to be well-tolerated in solid tumor malignancies. Cabozantinib was administered in 28 day cycles, and dose escalation occurred via 3 cohorts (40MG QD, 60MG QD, 80MG QD). Escalation to each successive dose level was guided by incidence of dose limiting toxicity (DLT) during cycle 1 of study treatment. Pharmacodynamic evaluation of serial plasma samples obtained from patients, by use of a plasma inhibitory assay (PIA), was used to assess FLT3 inhibitory activity in FLT3-ITDcell lines. Response was determined by bone marrow biopsy after the first cycle of treatment, and those achieving complete or partial remission, or with stable disease and clinical benefit, could continue on study until disease progression, intolerable toxicity, or upon receipt of 12 cycles.18 patients were enrolled on study. The median age was 68 (range 27-85); 12 (67%) were male, and 14 (78%) were Caucasian. FLT3-ITD mutations were detected in 5 (23%) patients, and NPM1 mutations in none. 16 patients (89%) had R/R AML, and 2 patients (11%) had newly diagnosed disease. The majority (75%) of those with R/R AML had been treated with two or more lines of prior treatment. 3 patients were enrolled at the first dose level (40MG QD), of whom one experienced >G3 transaminitis, thought unrelated to cabozantinib, but could not be dosed for this reason and was therefore replaced. No DLTs were detected at the first dose level among the 4 studied patients. However, two of the three patients enrolled at the second dose level (60MG QD) experienced DLT, one with grade 3 pancreatitis and the other with grade 3 transaminitis. Three patients were then enrolled at the next lower level, dose level 1 (40MG QD), of whom two could not complete the DLT period, one because of disease progression and the other due to an infected aortic ulceration unrelated to study treatment. These two patients were replaced, and no additional DLTs were noted. 40MG daily was therefore determined to be the MTD, and 6 patients were subsequently treated in an expansion cohort at this dose. Additional ≥ grade 2 toxicities, possibly or probably related to cabozantinib, each affected 3 or less patients, and included fatigue, nausea, anorexia, constipation, oral mucositis, palmar-plantar erythrodysesthesia, transaminitis, and electrolyte imbalance. Fifteen patients could be assessed for response on study. No patients had a marrow response per formal criteria. Four patients had a reduction in peripheral blasts during treatment, of whom 2 transiently cleared their circulating blasts (one with FLT3-ITD). One patient experienced a reduction in marrow blasts, and one had stable marrow disease. FLT3 inhibitory activity of serially collected patient plasma samples, as determined by the ex vivo PIA, consistently revealed potent and sustained inhibition of FLT3 auto-phosphorylation in FLT3-ITDmutant cell lines by day 8 of cycle 1.Cabozantinib, a multi-targeted TKI, is well-tolerated in patients with AML at the MTD of 40 MG daily. In this molecularly heterogeneous, heavily pre-treated population of AML patients, clinical response to cabozantinib monotherapy was limited. However, we found that cabozantinib inhibits FLT3-ITD tyrosine kinase in a potent and sustained fashion. Additional clinical study of cabozantinib among patients with FLT3 mutant AML is therefore warranted. DisclosuresFathi:Celgene: Consultancy, Research Funding; Merck: Other: Advisory Board participation; Seattle Genetics: Consultancy, Other: Advisory Board participation, Research Funding; Agios Pharmaceuticals: Other: Advisory Board participation; Bexalata: Other: Advisory Board participation. Levis:Millennium: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Daiichi-Sankyo: Consultancy, Honoraria; Astellas: Consultancy, Honoraria, Research Funding. Avigan:Astex: Research Funding; DCPrime: Research Funding. Hobbs:Constellation: Other: Advisory Board participation; Incyte: Other: Advisory Board participation.

Results of a Phase Ib Study of Venetoclax Plus R- or G-CHOP in Patients with B-Cell Non-Hodgkin Lymphoma

Results of a Phase Ib Study of Venetoclax Plus R- or G-CHOP in Patients with B-Cell Non-Hodgkin Lymphoma

Inappropriate dose of multitargeted tyrosine kinase inhibitors: the original sin.

The use of antiangiogenic tyrosine kinase inhibitors (TKIs) is challenging and often requires dose adaptation and transient or definitive treatment interruption. We believe that the inappropriate recommended dose of TKI is related to no optimal study designs in the early development of the drug. As an example of this, we described herein some pitfalls made in the successive development of sunitinib, sorafenib, regorafenib, and pazopanib, but there are several other examples of early drugs development illustrating this issue. Regarding the antiangiogenic TKI mechanism of action, we strongly feel that innovative approaches are needed such as extended dose-limiting toxicity period or a better definition of the induced toxicity. Furthermore, before classic phase II/III trials, an intermediate step may be needed to better define the recommended phase II dose, such as a randomized phase I/II trial with several expansion cohorts.