Modified Toxicity Probability Interval Research Articles

Abstract PS10-18: Phase Ib trial of olinvacimab and pembrolizumab in patients with metastatic triple-negative breast cancer

Abstract Background: Metastatic TNBC (mTNBC) has a poor prognosis. Preclinical data suggests benefit for combination therapy of immune checkpoint inhibitor and anti-angiogenesis. Olinvacimab (O) is a fully humanised monoclonal antibody (MAB) which binds to Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) and antiangiogenic and antitumor effects have been demonstrated. Pembrolizumab (P) is an anti-PD1 MAB. This study aimed to identify the safety and tolerability of O and P to establish a phase 2 recommended dose of O. Methods: From December 2018 to September 2020, we conducted a two-site, single arm, open-label study of O and P in pts with mTNBC. Eligible patients (pts) were >18 years, had ER, PR & HER2-negative MBC with at least one measurable lesion and adequate organ function. Pts with history of serious thromboembolism, gastrointestinal haemorrhage and prior anti-VEGF therapy were excluded. A modified Toxicity Probability Interval design was used. Pts received O 12 mg/kg q7d (dose level 1) or 16mg/kg day q7d (dose level 2) in combination with P 200mg flat dose day 1 q21d. Treatment continued until dose limiting toxicity (DLT), disease progression (PD) or treatment intolerance. Results: 11 pts, median age 62 (range 39-67) were recruited and received at least one dose of treatment. 8 (73%) had ECOG PS 1 and 3 (27%) had ECOG PS 2. 5 pts had previous chemotherapy for mTNBC (with 3 pts also having received immunotherapy), 6 pts were treated in the first-line metastatic setting (with all pts having received anthracycline and taxane in the adjuvant setting). 5 pts received O at 12mg/kg with P, completing a median of 6 cycles (range 1-18). As no DLTs were seen, 6 pts were treated with O at 16mg/kg with median of 8 cycles (range 2-21), with no DLTs being observed. Treatment was ceased due to PD in 6 pts, 3 pts are receiving treatment at data cut-off. Haemangiomas were seen in 8 pts accounting for 47 events of CTCAE grade 1 and 21 events of grade 2. Treatment emergent adverse events (TEAEs) of ≥grade 3 was seen in 6 pts (27 events), with 8 events being related to treatment. 4 pts (36%) had partial response (PR) as best overall response 5 pts (45%) had clinical benefit (PR+SD≥24weeks). Conclusions: Combination therapy of O and P was well tolerated with evidence of efficacy in mTNBC pts who had all previously received anthracycline and taxanes, with 3 pts having previously received immunotherapy. These results support the combination entering into a phase 2 study. Citation Format: Arlene Chan, Eugene Moylan, Sally Jackson, Jeannette Devoto, Nicola Jones, Silvie Radmil, Kate Wilkinson, Aflah Roohullah, Tamiem Adam, Seon Young Lee, Weon Sup Lee, Jin-San Yoo. Phase Ib trial of olinvacimab and pembrolizumab in patients with metastatic triple-negative breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS10-18.

KRYSTAL-2: A phase I/II trial of adagrasib (MRTX849) in combination with TNO155 in patients with advanced solid tumors with KRAS G12C mutation.

TPS146 Background: KRAS is the most frequently mutated oncogene in cancer and a key mediator of the RAS/MAPK signaling cascade that promotes cellular growth and proliferation. KRAS G12C tumor mutations occur in approximately 14% of patients with lung adenocarcinoma and 3-4% of colorectal adenocarinoma. SHP2 is a phosphatase that acts as a key mediator of signaling from receptor tyrosine kinases (RTKs) to downstream RAS/MAPK pathways. Adagrasib (MRTX849) is a specific small-molecule investigational inhibitor of KRAS G12C that covalently binds to and locks mutant KRAS in its GDP-bound inactive form. Adagrasib has been optimized for a long half-life and extensive tissue distribution to enable inhibition throughout the entire dosing interval. Preliminary results from a Phase 1/2 study of adagrasib demonstrated promising antitumor activity and tolerability across multiple KRAS G12C tumor types. TNO155 is a selective inhibitor of SHP2 with demonstrated inhibition of RTK signaling and significant antitumor activity in preclinical models. Preclinical studies have shown that resistance to KRAS G12C inhibition may be mediated by SHP2-dependent feedback loops. Because KRAS G12C retains some level of cycling between GTP- and GDP-bound states, KRAS G12C that is not bound by inhibitor can activate downstream signaling. Active SHP2 functions to increase the active state of RAS proteins (including mutant KRAS) and also increases ERK pathway activation. Therefore, the addition of TNO155 to adagrasib may augment antitumor activity and overcome resistance by inhibiting cycling to GTP-bound KRAS and/or through inhibition of feedback activation and more comprehensively inhibiting downstream ERK signaling. In KRAS G12C human tumor models, adagrasib combined with a SHP2 inhibitor demonstrated greater activity compared to each agent alone. These data provide support for clinical evaluation of this combination in KRAS G12C tumors. Methods: KRYSTAL-2 is a multicenter Phase 1/2 study evaluating adagrasib and TNO155 in patients with advanced solid tumors harboring a KRAS G12C mutation. Overall objectives of the trial include evaluating safety, tolerability, and PK. The Phase 1 portion will evaluate adagrasib and TNO155 utilizing a modified Toxicity Probability Interval dose escalation design to identify maximum tolerated dose and recommended Phase 2 dose. The Phase 2 portion utilizes a Simon's optimal two-stage design to evaluate the clinical activity of adagrasib with TNO155 in 2 cohorts of up to 108 patients—CRC (54 patients) and NSCLC (54 patients). Efficacy endpoints include Objective Response Rate (RECIST 1.1), Duration of Response (DOR), Progression-free Survival (PFS), and Overall Survival (OS). The study is currently enrolling and patients will receive study treatment until disease progression, unacceptable adverse events, patient withdrawal, or death. Clinical trial information: NCT04330664.

Preliminary Safety, Efficacy, Pharmacokinetics, and Pharmacodynamics of Subcutaneously (SC) Administered PF-06863135, a B-Cell Maturation Antigen (BCMA)-CD3 Bispecific Antibody, in Patients with Relapsed/Refractory Multiple Myeloma (RRMM)

Preliminary Safety, Efficacy, Pharmacokinetics, and Pharmacodynamics of Subcutaneously (SC) Administered PF-06863135, a B-Cell Maturation Antigen (BCMA)-CD3 Bispecific Antibody, in Patients with Relapsed/Refractory Multiple Myeloma (RRMM)

Results from a Phase 1 Dose Escalation Study of HMPL-689, a Selective Oral Phosphoinositide 3-Kinase-Delta Inhibitor, in Chinese Patients with Relapsed/Refractory (R/R) Lymphomas

Introduction HMPL-689 is a potent and highly selective small molecule inhibitor of phosphoinositide 3-kinase-delta (PI3Kδ). Despite available agents targeting the B-cell receptor (BCR) pathway, there remains a need for alternative therapies in the relapsed/refractory (R/R) setting due to agent-specific toxicities and suboptimal efficacy among lymphoma subtypes. This study (NCT03128164) is a phase 1, open-label, dose escalation and expansion study in China to assess the safety, pharmacokinetics (PK), and preliminary efficacy of HMPL-689 as a monotherapy in patients with R/R lymphomas. Here we present the preliminary results of the dose-escalation phase of the study. Methods In this dose escalation phase, patients with R/R lymphoma failed of standard therapy, at least 1 prior therapy, were eligible. The dose-escalation study consisted of cohort A (BID) and cohort B (QD), in which HMPL-689 was orally administered continuously on a 28-day cycle. The modified toxicity probability interval scheme-2 (mTPI-2) design was applied for the dose escalation and maximum tolerated dose (MTD) determination. Blood samples for PK and pharmacodynamics (PD) analyses were collected during Cycle 1 and Day 1 of each subsequent cycle. Results A total of 56 patients were enrolled, with 5 chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), 23 follicular lymphoma (FL), 7 marginal zone lymphoma (MZL), 9 mantle cell lymphoma (MCL), 9 diffuse large B cell lymphoma (DLBCL), and 3 Hodgkin's lymphoma (HL) patients (Table 1). The median age was 56 years (range 26-73). The median number of prior therapies was 3 (range 1-8), of which 39 patients had prior exposure to rituximab. 29 patients received HMPL-689 in cohort A (BID): 2.5 mg (n=3), 5 mg (n=9), 7.5 mg (n=8), and 10 mg (n=9), while 27 patients were in cohort B (QD): 5 mg (n=3), 10 mg (n=3), 20 mg (n=9), 30 mg (n=9), and 40 mg (n=3). Median duration of HMPL-689 therapy was 7.6 months (range 0.4 -Not reached [NR]). The most common Grade ≥3 non-hematologic treatment emergent adverse events (TEAEs) were pneumonia and hypertension. Grade ≥3 hematologic TEAEs were neutropenia (Table 2). No Grade 5 TEAE was reported. In cohort A, 4 dose limited toxicities (DLTs) were observed, including Grade 3 asymptomatic amylase (2 pts, 5 mg), Grade 4 hypercalcemia (1 pt, 10 mg), Grade 3 lipase increased (1 pt, 10 mg). In cohort B, 5 DLTs including Grade 3 skin maculopapular (1 pt, 20 mg), hypertriglyceridemia (1 pt, 30 mg), QT interval prolongation (1 pt, 30 mg) and rash (2 pts, 40 mg) were reported. Plasma PK data for the 5-30 mg QD and 2.5-10 mg BID multiple-dose regimens were determined. HMPL-689 drug exposures increased in a dose proportional fashion up to 30mg QD, as reflected in AUC and Cmax. The geometric mean AUCtau and Cmax at 30 mg QD in patients were approximately 2150 h•ng/mL and 260 ng/mL, respectively at steady state. The median Tmax was around 2 h and the arithmetic mean t1/2 was within the range of 5-10 hours, consistent across all dose levels. 51 out of the 56 patients had post-baseline tumor assessment, with 6 complete response (CR) (2 CLL/SLL, 4 FL), 21 partial responses (PR) (2 CLL/SLL, 5 MZL, 7 FL, 4 MCL, 3 DLBCL) and 18 stable disease (SD) (2 MZL, 9 FL, 4 MCL, 1 DLBCL, 2 HL). This resulted in 52.9% (27/51) objective response rate (ORR) in efficacy evaluable patients. The median time to response (TTR) and duration of response (DOR) were 3.5 months (1.8-8.4) and 6.4 months (0.7-NR), respectively (Table 3). One patient with FL who achieved CR (per post hoc independent radiologic review) was on treatment > 586 days. Final data quality control/verification is ongoing. As a result, 30 mg QD of HMPL-689 has been selected as recommended phase 2 dose (RP2D) based on overall safety and tolerability, PK/PD and preliminary efficacy data. Conclusions: HMPL-689 was well tolerated and the RP2D was determined to be 30 mg QD orally. It exhibited dose-proportional pharmacokinetics, a manageable toxicity profile, and promising single-agent clinical activity in R/R B-cell lymphoma patients. The dose expansion study is ongoing, evaluating the safety and efficacy of HMPL-689 in patients with R/R B-cell lymphoma. Acknowledgement 1. We would like to thank all patients and their families who participated in this trial; 2. We would like to thank all investigators, study coordinators and the entire project team. Disclosures Duan: Hutchison MediPharma Limitied: Current Employment. Yu:Hutchison MediPharma Limitied: Current Employment. Cai:Hutchison MediPharma Limitied: Current Employment. Su:Hutchison MediPharma Limited: Current Employment.

Rationale for and Results of a Phase I Study of the TGF-β 1/3 Inhibitor AVID200 in Subjects with Myelofibrosis: MPN-RC 118 Trial

Rationale for and Results of a Phase I Study of the TGF-β 1/3 Inhibitor AVID200 in Subjects with Myelofibrosis: MPN-RC 118 Trial

Transcend CLL 004: Phase 1 Cohort of Lisocabtagene Maraleucel (liso-cel) in Combination with Ibrutinib for Patients with Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL)

Transcend CLL 004: Phase 1 Cohort of Lisocabtagene Maraleucel (liso-cel) in Combination with Ibrutinib for Patients with Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL)

Design considerations for phase I/II dose finding clinical trials in Immuno-oncology and cell therapy

Immuno-oncology (IO) and cell therapy, the frontier of cancer treatment, is a rapidly developing area that brings new opportunities to patients. In IO and cell therapy clinical trial development, it is critical to identify the right dose level in early phase of trials thus improving the probability of success in confirmatory trials to test the superiority over other therapies. Given the complex mechanism interacting with immune system for IO drugs especially cell therapy, the traditional oncology dose finding trial designs may not serve the purpose. Specifically, it is questionable to believe the monotone relationship between dose level and safety/efficacy, which will likely result in inappropriate dose selection using designs with monotone assumption. Additionally, considering the immune system pathway, designs ignoring the heterogeneity of the patient populations may provide misleading dose decisions, which could be either unsafe or lead to selection mistakes for targeted population. Therefore, in our paper, we review and present the limitations of the traditional dose finding designs. Then we discuss improved dose finding designs that consider both safety and efficacy outcomes simultaneously. Furthermore, we propose novel dose finding designs for multiple populations: BNP-mTPI and fBNP-mTPI, which extend the modified toxicity probability interval designs by utilizing Bayesian non-parametric priors. The proposed designs consider patient population differences meanwhile flexibly borrowing information across populations with similar profiles to improve the efficiency of dose search and accuracy of estimation of optimal dose level. Simulations are provided to demonstrate the model performance. Finally, we conclude the recommendations for IO and cell therapy dose finding designs in the discussion and offer insights for future research direction.

A comparison of phase I dose-finding designs in clinical trials with monotonicity assumption violation.

In oncology, new combined treatments make it difficult to order dose levels according to monotonically increasing toxicity. New flexible dose-finding designs that take into account uncertainty in dose levels ordering were compared with classical designs through simulations in the setting of the monotonicity assumption violation. We give recommendations for the choice of dose-finding design. Motivated by a clinical trial for patients with high-risk neuroblastoma, we considered designs that require a monotonicity assumption, the Bayesian Continual Reassessment Method, the modified Toxicity Probability Interval, the Bayesian Optimal Interval design, and designs that relax monotonicity assumption, the Bayesian Partial Ordering Continual Reassessment Method and the No Monotonicity Assumption design. We considered 15 scenarios including monotonic and non-monotonic dose-toxicity relationships among six dose levels. The No Monotonicity Assumption and Partial Ordering Continual Reassessment Method designs were robust to the violation of the monotonicity assumption. Under non-monotonic scenarios, the No Monotonicity Assumption design selected the correct dose level more often than alternative methods on average. Under the majority of monotonic scenarios, the Partial Ordering Continual Reassessment Method selected the correct dose level more often than the No Monotonicity Assumption design. Other designs were impacted by the violation of the monotonicity assumption with a proportion of correct selections below 20% in most scenarios. Under monotonic scenarios, the highest proportions of correct selections were achieved using the Continual Reassessment Method and the Bayesian Optimal Interval design (between 52.8% and 73.1%). The costs of relaxing the monotonicity assumption by the No Monotonicity Assumption design and Partial Ordering Continual Reassessment Method were decreases in the proportions of correct selections under monotonic scenarios ranging from 5.3% to 20.7% and from 1.4% to 16.1%, respectively, compared with the best performing design and were higher proportions of patients allocated to toxic dose levels during the trial. Innovative oncology treatments may no longer follow monotonic dose levels ordering which makes standard phase I methods fail. In such a setting, appropriate designs, as the No Monotonicity Assumption or Partial Ordering Continual Reassessment Method designs, should be used to safely determine recommended for phase II dose.

A phase Ib study of ribociclib in combination with doxorubicin in advanced soft tissue sarcomas (aSTS).

11548 Background: aSTS are typically treated with single agent doxorubicin (dox). CDK4 inhibitors such as ribociclib (ribo) may have a role in treating STS, which frequently rely on hyperphosphorylation of Rb to evade the Rb checkpoint. We hypothesized that dox efficacy could be increased by inhibiting Rb phosphorylation with a short course of ribo, then removing ribo to permit cell cycle progression prior to dox, thus potentiating the DNA-damaging effects of dox. Methods: Open label, dose-finding study of ribo and dox in dox-naïve patients (pts) with Rb+ aSTS. Rb status determined by IHC. Primary objective to determine the recommended phase 2 dose (RP2D). Secondary objective of anti-tumor activity. Pts received ribo 400-600 mg PO QD x7d followed by 72h rest before dox 60-75 mg/m2 IV, q21d. Pts free from progression of disease after 6 cycles continued on ribo maintenance at 600 mg QD q3/4wk. Dose-limiting toxicity (DLT) period was cycle 1, with target toxicity rate of 30% using a modified toxicity probability interval (mTPI) design. Growth factor support was not allowed during DLT period. Results: 9 screened pts were ineligible by Rb status. 16 pts enrolled with 15 evaluable for dose determination (7 dedifferentiated LPS, 8 other subtypes). 4 of 7 pts treated at starting dose level (400 mg ribo, 75 mg/m2 dox) had a DLT; all febrile neutropenia. 1 of 8 pts treated at dose level -1 (400 mg ribo, 60 mg/m2 dox) had a DLT of gr4 anemia. Febrile neutropenia events occurred during cycle 1, when growth factors were prohibited. Toxicity was similar to historical dox AEs (Table). Two partial responses for overall response rate (ORR) of 13%. Five (33%) were progression-free at 18 wks. Correlative studies ongoing. Conclusions: This study determined a RP2D of ribo 400 mg with dox 60 mg/m2 when used in combination for the treatment of aSTS. Clinical trial information: NCT03009201 . [Table: see text]

DREAMM-5 platform trial: Belantamab mafodotin in combination with novel agents in patients with relapsed/refractory multiple myeloma (RRMM).

TPS8552 Background: Single-agent belantamab mafodotin (GSK2857916), a B-cell maturation antigen targeting immunoconjugate, induced deep and durable responses in patients with RRMM, with a manageable safety profile (DREAMM-2, NCT03525678, Lancet Oncol.2020). A platform trial design allows efficient evaluation of belantamab mafodotin in combination with other anti-myeloma agents, such as a humanized wild-type IgG1 anti-OX40 agonist, an IgG4 inducible T-cell costimulatory (ICOS) agonist, and a gamma-secretase inhibitor. The unique, multimodal mechanisms of action (MoAs) of belantamab mafodotin, in combination with MoAs of these agents, has the potential to achieve synergistic effects in MM, to further enhance anti-myeloma activity without compromising safety. Methods: DREAMM-5 (NCT04162210) utilizes a master protocol with separate sub-studies comprised of sequential dose exploration (DE) and cohort expansion (CE) phases, to identify promising, effective belantamab mafodotin combinations when compared with a shared belantamab mafodotin monotherapy control arm (CE phase only). DE phases consist of multiple dosing cohorts with belantamab mafodotin combinations where patients are assigned to treatment slots by predetermined algorithmic approach (modified toxicity probability interval; N≤10 per cohort). Recommended phase 2 doses (RP2D) will be based on dose-limiting toxicities, safety, and pharmacokinetics. Interim analyses, based on overall response rate (ORR), determine if a RP2D is moved forward to a CE phase (N≥35 per cohort). Patients in the CE (stratified by number of prior therapies) will be randomized equally to open sub-studies. Eligible patients will have received ≥3 prior therapy lines which must include ≥1 immunomodulatory agent, proteasome inhibitor, and anti-CD38 antibody. The primary objectives are to identify RP2D for each combination (DE phase) and ORR (≥partial response, CE phase). Sub-studies 1 (combination with GSK3174998, OX40 agonist antibody) and 2 (combination with GSK3359609, ICOS agonist antibody) are currently enrolling. Sub-study 3 (combination with nirogacestat [PF-03084014; SpringWorks Therapeutics]) is projected to begin enrollment in the first half of 2020. Additional sub-studies will be explored based on scientific rationale and/or preclinical combination study results. Funding: GlaxoSmithKline (207495). Drug linker technology licensed from Seattle Genetics; monoclonal antibody produced using POTELLIGENT Technology licensed from BioWa. Clinical trial information: NCT04162210 .

DREAMM-9: Phase III study of belantamab mafodotin plus VRd versus VRd alone in transplant-ineligible newly diagnosed multiple myeloma (TI NDMM).

TPS8556 Background: Bortezomib, lenalidomide, and dexamethasone (VRd) is the standard of care for transplant-eligible and TI NDMM, but relapse is usually inevitable. The median progression-free survival (PFS) is ~3 years for patients with TI NDMM, and with each relapse, the duration of response (DoR) diminishes, highlighting the need for novel, effective, targeted agents. Single-agent belantamab mafodotin is a first-in-class B-cell maturation antigen–binding, humanized, afucosylated, monoclonal immunoconjugate, showing deep and durable responses in heavily pretreated patients with relapsed/refractory multiple myeloma ( Lancet Oncol2020). Preclinical work suggests belantamab mafodotin plus bortezomib or lenalidomide enhances anti-myeloma activity. Therefore, studying clinical activity of belantamab mafodotin in combination with these agents is warranted. Methods: DREAMM-9 (NCT04091126) is a two-part, open-label study to determine efficacy and safety of single-agent belantamab mafodotin with VRd vs. VRd alone in patients with TI NDMM. Patients aged ≥18 years with ECOG status 0–2 and adequate organ system functions will be eligible. Part 1 (dose selection) will evaluate safety/tolerability of belantamab mafodotin with VRd administered by single (Day 1) or split dosing (Days 1 and 8) in ≤5 cohorts (n = 12/cohort): 1.9 mg/kg, 2.5 mg/kg split and single, and 3.4 mg/kg split and single. Six more patients may be added to cohort(s) most likely to be selected as recommended Phase III dose (RP3D). Dose-limiting toxicities and adverse events (AEs) will be assessed, and belantamab mafodotin RP3D determined through modified toxicity probability interval criteria. Part 2 (randomized Phase III) will determine efficacy and safety of belantamab mafodotin at RP3D with VRd vs. VRd alone (n = 750) in two arms randomized 1:1. Dual primary endpoints will be rate of minimal residual disease (MRD) negativity and PFS. Secondary endpoints will be response rates (overall response, complete response, very good partial response or better, sustained MRD negativity), DoR, time to progression, and overall survival. Safety assessment will include AEs, serious AEs and ocular findings. In both parts, belantamab mafodotin will be given with VRd for eight induction cycles and then with Rd for maintenance until disease progression or unacceptable toxicity. Funding: GlaxoSmithKline (209664). Drug linker technology licensed from Seattle Genetics; monoclonal antibody produced using POTELLIGENT Technology licensed from BioWa. Clinical trial information: NCT04091126 .

SGN228-001: A phase I open-label dose-escalation, and expansion study of SGN-CD228A in select advanced solid tumors.

TPS3652 Background: SGN-CD228A is an investigational antibody-drug conjugate (ADC) that targets CD228, a cell-surface oncofetal protein with prevalent expression in several types of cancer and limited expression on normal tissues. SGN-CD228A consists of a humanized IgG1 anti-CD228 monoclonal antibody conjugated to an average of 8 molecules of monomethyl auristatin E (MMAE) via a PEGylated β-glucuronidase cleavable linker. MMAE is a well-studied and highly active chemotype with an established safety profile. The proposed mechanism of action involves binding CD228 on cell surfaces, ADC internalization, and trafficking to lysosomes. MMAE is then released through β-glucuronidase cleavage of the glucuronide MMAE linker. MMAE then binds tubulin, which disrupts microtubule networks and causes cell cycle arrest and apoptosis. Methods: SGN228-001 (NCT04042480) is a phase 1, open label, multicenter, dose escalation, and expansion study enrolling up to 240 subjects to evaluate the safety, tolerability, PK, and antitumor activity of SGN-CD228A in select advanced solid tumors. Eligible subjects are ≥18 years of age and have metastatic cutaneous melanoma, malignant pleural mesothelioma, human epidermal growth factor receptor 2-negative metastatic breast cancer, advanced non-small cell lung cancer, metastatic colorectal cancer, or advanced pancreatic ductal adenocarcinoma. Subjects must have relapsed, refractory, or progressive disease, and should have no appropriate standard therapy available. Measurable disease per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1), Eastern Cooperative Oncology Group (ECOG) performance status score of ≤1, and adequate renal, hepatic, and hematologic function are required. The study includes dose escalation and dose expansion, with multiple disease-specific dose expansion cohorts and a biology cohort. Dose escalation will be conducted using the modified toxicity probability interval method (Ji 2010) to evaluate the safety and identify the maximum tolerated dose of SGN-CD228A. Following dose escalation, disease-specific expansion cohorts and a biology cohort (to evaluate exploratory biomarkers) are planned. Response assessments will be conducted every 6 weeks per RECIST v1.1 and all subjects will be followed for safety. Pharmacokinetics and markers of pharmacodynamics will be assessed regularly. Key efficacy endpoints include objective response rate, progression-free survival, and duration of objective response. Enrollment is ongoing in the US and planned in Europe. Clinical trial information: NCT04042480 .

Phase Ib study of olinvacimab (O) with pembrolizumab (P) in patients with recurrent glioblastoma (rGBM).

e14545 Background: Recurrent GBM is difficult to treat. Single agent checkpoint blockade has not improved outcomes. Angiogenesis is a rational drug target for rGBM and targeting angiogenesis may benefit pseudoprogression and cerebral oedema. O is a fully human monoclonal antibody (MAB) which binds to Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) with antiangiogenic and antitumour effects. P is an anti-PD1 MAB. This study aimed to identify the safety and tolerability of O combined with P and to establish a recommended phase 2 combination dose. Methods: From January to October 2019, we conducted a two-site, single arm, open-label study of O with P in patients with rGBM. Eligible patients (pts) were ≥18 years with at least one RANO-measurable lesion, KPS≥80, and had completed standard chemoradiotherapy and had no contraindications to O or P. No prior bevacizumab was allowed. A modified Toxicity Probability Interval design was used. Pts received O 12 mg/kg day 1/8/15 q21d (dose level 1) or O 16mg/kg day 1/8/15 q21d (dose level 2) in combination with P 200mg flat dose day 1 q21d. Pts were reviewed weekly and underwent DCE-MRI at baseline and 6-weekly. Treatment continued to progression, toxicity or withdrawal. Results: 9 pts, median age 53 (range 34-67) were recruited and received at least one study treatment. Median time since diagnosis was 15.6 months. 7 (78%) had KPS 90 and 2 (22%) KPS 80. 3 pts received O 12mg/kg with P, completing a median 3 cycles (range 2-6). As no Dose Limiting Toxicities (DLTs) were seen, 3 pts were treated with O 16mg/kg with expansion total 6 when no DLTs were observed. At 16mg/kg, a median of 2 treatment cycles was received (range 2-6). Treatment was ceased due to progressive disease (PD) in 8 pts with one ongoing at data cutoff. No DLTs were observed in any pts. Three grade 3 treatment emergent adverse events (TEAEs) were noted (blurred vision, fatigue, and seizure). Hemangioma is a known toxicity of O and was seen in 6 pts, with 11 grade 1 and 1 grade 2 event. 4 pts (44%) had stable disease (SD) and 5 pts (56%) had PD as best response. Conclusions: The combination of O with P was safe and tolerable at the full single agent dose of each drug. No DLTs were observed. The combination did not show efficacy in this setting. Clinical trial information: NCT03722342.

SGNLVA-001: A phase I open-label dose escalation and expansion study of SGN-LIV1A administered weekly in breast cancer.

TPS1104 Background: LIV-1 is a highly prevalent transmembrane protein in breast cancer cells. Ladiratuzumab vedotin (LV), SGN-LIV1A, is an investigational antibody-drug conjugate (ADC) that targets LIV-1 via a humanized IgG1 monoclonal antibody conjugated to monomethyl auristatin E (MMAE) by a protease-cleavable linker. LV is internalized when it binds LIV-1 on cell surfaces and MMAE is released, which binds tubulin and induces apoptosis. LV has been shown to be active and tolerable in metastatic breast cancer (mBC) at a recommended dose of 2.5 mg/kg every 21 days (Modi 2017). More frequent, fractionated dosing has improved the activity and/or safety of other ADCs. Thus, this study is actively accruing subjects with metastatic triple negative breast cancer (mTNBC; estrogen receptor (ER)/progesterone receptor (PR)/human epidermal growth factor receptor 2 (HER2) receptor-negative) and endocrine-resistant ER+ or PR+ (hormone receptor [HR+])/HER2-negative mBC to test weekly dosing of LV (Days 1, 8, and 15 of every 3-week cycle). Methods: This study is enrolling up to 82 subjects (42 HR+/HER2-negative and 40 mTNBC) into dose escalation and dose expansion cohorts (NCT01969643). Eligible subjects are females ≥18 years old with pathologically and radiologically confirmed metastatic HR+/HER2-negative or mTNBC with at least 1 measurable lesion per RECIST v1.1. Subjects with HR+/HER2-negative disease must have received no more than 1 prior line of cytotoxic chemotherapy in the locally advanced (LA)/mBC setting, either as single agent or combination therapy. Subjects with mTNBC must have received 1 prior line of cytotoxic chemotherapy in the LA/mBC setting. Progression within 6 months of completion of neoadjuvant or adjuvant therapy is considered an LA/mBC regimen. Subjects must have adequate organ function, ECOG status of ≤1, and no ≥ Grade 2 peripheral neuropathy. Subjects with brain lesions must have received definitive treatment of the lesions. Prior therapy with MMAE-containing agents is not allowed. Dose escalation follows the modified toxicity probability interval method (Ji 2010). Dose expansion cohorts will provide data about activity and tolerability. Tumor assessments will be conducted every 2 cycles per RECIST v1.1 and all subjects will be followed for safety. Pharmacokinetics and markers of pharmacodynamics will be assessed. Primary safety endpoint is the incidence of adverse events and dose-limiting toxicities. Key efficacy endpoints include confirmed overall response rate, duration of response, and progression-free survival. Clinical trial information: NCT01969643 .

A phase I study of guadecitabine (SGI-110) plus cisplatin in patients with platinum refractory germ cell tumors.

408 Background: Guadecitabine (SGI-110) is a novel hypomethylating dinucleotide of decitabine and deoxyguanosine resistant to degradation by cytidine deaminase. Platinum-refractory germ cell tumors (GCT) showed significant DNA hypermethylation compared to platinum sensitive tumors. In preclinical studies, GCT were extremely sensitive to low dose decitabine which restored sensitivity to cisplatin in cell lines. We aimed to assess the safety and clinical activity of guadecitabine in combination with cisplatin in patients with platinum-refractory GCT. Methods: In this open-label, phase 1 study, patients with GCT refractory to or had relapsed after platinum-based treatment were treated with subcutaneous (SQ) guadecitabine, once-daily for 5 consecutive days, followed by cisplatin on day 8 with growth factor support (GFS) in a 28-day treatment cycle. A modified toxicity probability interval (mTPI) dose-escalation design was used in which we treated patients with guadecitabine doses of 30-45 mg/m2 plus cisplatin 100 mg/m2 up to 6 cycles until progression or intolerable toxicity. The primary objective was to assess safety and tolerability of the combination, determine the maximum tolerated dose (MTD). Secondary objective was objective response rate (ORR). Results: Fourteen patients with incurable disease were enrolled. Primary site were testis 11, mediastinum 2, and ovarian 1. All progressed after at least 2 lines of standard of care chemotherapy including HDCT. Dose-limiting toxicities were neutropenic fever. Most common toxicities were neutropenia (82% any grade), thrombocytopenia (42%), anemia (33%), neutropenic fever (8%), and diarrhea (8%). The maximum tolerated dose of guadecitabine was 30 mg/m2 x 5 days and cisplatin 100 mg/m2. We observed 2/14 complete response lasting more than 6 months, 2 partial response and 1 stable disease. ORR 28.5%. Conclusions: We report the first study of chemo-priming with epigenetic therapy in GCT. Guadecitabine 30 mg/m2 x 5 days and cisplatin 100 mg/m2 with GFS was safe and tolerable and showed promising activity with 4/14 responses in this highly treatment refractory patient population. Clinical trial information: NCT02429466.

MEDI3726, a prostate-specific membrane antigen (PSMA)-targeted antibody-drug conjugate (ADC) in mCRPC after failure of abiraterone or enzalutamide.

99 Background: MEDI3726 is an ADC targeting PSMA. Once bound to PSMA and internalized, the released pyrrolobenzodiazepine dimer toxin crosslinks DNA and triggers cell death. This phase 1 study evaluated the safety and efficacy of MEDI3726 in mCRPC after failure of abiraterone and/or enzalutamide and a taxane-based therapy. Methods: The starting dose was 0.015 mg/kg MEDI3726 IV Q3W until disease progression or unacceptable toxicity. Dose escalation used a modified toxicity probability interval algorithm (mTPI). The primary objectives were safety, adverse events (AEs) and dose-limiting toxicities (DLTs) and to determine the maximum tolerated (MTD) or administered (MAD) dose. Secondary objectives included antitumor activity, pharmacokinetics and immunogenicity. The endpoint for activity was composite response: confirmed response by RECIST v1.1, and/or PSA decrease of ≥ 50% after ≥ 12 wks, and/or confirmed conversion in circulating tumor cell count, defined as a decrease from ≥ 5 to < 5 cells/7.5 mL. Efficacy analyses were based on Prostate Working Group Criteria. Mutational profiles were evaluated in ctDNA. Results: As of Sept 27 2019, 33 pts received MEDI3726. Median age was 71.0 yr. Median number of prior regimens was 4. Median follow-up was 5.4 mo. Drug-related AEs occurred in 30 (90.9%), being grade 3/4 in 15 (45.5%), serious in 11 (33.3%) and causing discontinuation in 13 (39.4%). There were no drug-related deaths. One pt at 0.3 mg/kg had a DLT of Grade 3 thrombocytopenia. No MTD was identified per mTPI; the MAD was 0.3 mg/kg. MEDI3726 had nonlinear PK with a short t1/2 (0.3–2 d). Three pts (15.8%) at baseline and 6 (33.3%) post-baseline had antidrug antibodies, with no correlation to PK exposure. Composite response rate across all doses was 2/33 (6.1%). Time to response was 0.3 mo; duration of response was 1.8–3.8 mo. Median progression-free survival was 3.9 mo and median overall survival was 10.6 mo. Conclusions: An MTD was not identified, but drug-related AEs (skin toxicities and effusions) prevented raising the dose over 0.3 mg/kg and limited the number of cycles. Responses were seen at higher doses, but were not durable as pts discontinued due to drug-related AEs. Clinical trial information: NCT02991911.

Phase Ib study of regorafenib (REG) plus pembrolizumab (PEMBRO) for first-line treatment of advanced hepatocellular carcinoma (HCC).

564 Background: REG is a multikinase inhibitor with immunomodulatory activity and PEMBRO is an anti-PD-1 monoclonal antibody. Both are approved as monotherapy for patients (pts) with HCC previously treated with sorafenib. Based on their potential synergistic effects, we conducted a phase 1b study of REG plus PEMBRO for first-line treatment of advanced HCC. Methods: This is an ongoing, open-label, dose-escalation study in pts with advanced HCC who had no prior systemic therapy. In the first cohort, pts received REG 120 mg/day PO for 3 weeks on/1 week off plus PEMBRO 200 mg IV q 3 weeks. In later cohorts, the REG dose could be escalated (160 mg) or reduced (80 mg) based on the modified toxicity probability interval design; the PEMBRO dose is fixed. The primary objective is safety and tolerability. Secondary objectives are to define the maximum tolerated dose (MTD) and recommended phase 2 dose, and to assess antitumor activity. Results: As of August 23, 2019, 29 pts have been treated at the REG 120 mg level. Median age is 65 years (range 32–81); 41%/55% of pts are BCLC stage B/C; 100% are Child–Pugh A; ECOG status 0/1 is 72%/28%. Dose-limiting toxicities occurred in 4/18 evaluable pts: grade (Gr) 3 increased ALT/AST with Gr 2 increased bilirubin (n = 2); Gr 3 rash (n = 2). The MTD of REG in the combination was 120 mg. Most common Gr 3 or 4 treatment-emergent adverse events (TEAEs) are shown (n = 29). There were no Gr 5 TEAEs. 59%/31% of pts had REG/PEMRO-related Gr 3 or 4 TEAEs. Dose modifications (reductions or interruptions) of REG/PEMBRO for drug-related TEAEs occurred in 59%/31% of pts. Of 23 evaluable pts, 7 (30%) had a partial response (PR) and 14 (61%) had stable disease (RECIST v1.1); 1 additional pt had PR by mRECIST. Conclusions: The combination of REG plus PEMBRO for first-line treatment of advanced HCC showed no unexpected safety signals and encouraging antitumor activity. Accrual is continuing at REG 120 mg dose and an expansion cohort evaluating REG 80 mg plus PEMBRO is planned. Clinical trial information: NCT03347292. [Table: see text]

First in Human Study of SEL24/MEN1703, First in Class, Orally Available Dual PIM/FLT3 Kinase Inhibitor, in Patients with Acute Myeloid Leukemia

Introduction SEL24/MEN1703 is a potent dual inhibitor of proviral integration site for Moloney murine leukemia virus (PIM) and FMS-like tyrosine kinase 3 (FLT3) with increased activity in both primary Acute Myeloid Leukemia (AML) cells and AML cell lines, irrespectively of FLT3 mutational status, when compared to either FLT3 or PIM single agent inhibitors. PIM kinases are thought to be major drivers of resistance to FLT3 inhibitors and their inhibition in relapsed samples restores cell sensitivity to these agents. Thus, simultaneous PIM and FLT3 inhibition represents a promising strategy in AML therapy. In addition, the broader spectrum of activity of SEL24/MEN1703, which goes beyond PIM/FLT3 inhibition, warrants the compound investigation in AML patients regardless of the genetic aberrations of FLT3. Methods CLI24-001 is a First-in-Human, single-arm, phase I/II trial with a dose-escalation (DE) part followed by a cohort expansion (CE) part in patients with AML (excluding Acute Promyelocytic Leukemia) -newly diagnosed, relapsed or refractory - that are unsuitable for intensive chemotherapy and meet the main inclusion criterion of white blood count (WBC) of ≤30 x 109/L (hydroxyurea/leukapheresis permitted to lower WBC). In both study parts, patients are eligible regardless of mutational status and prior exposure to FLT3 inhibitors; however, prior treatment with PIM inhibitors is not allowed. SEL24/MEN1703 is given orally, QD, for 14 days in a 21-day cycle to be repeated until disease progression, or unacceptable toxicity or withdrawal of patient consent. Bayesian modified toxicity probability interval model was implemented in the DE part after achieving 5 incremental dose levels in order to provide the most accurate identification of the Recommended Phase 2 Dose (RP2D). Also, during the DE part, a new oral formulation was introduced and compared to the original one by repeating the 100 mg dose level in order to avoid a subsequent formal bioequivalence study in patients. The primary objective of the study is to identify the RP2D of SEL24/MEN1703 in the DE part that will be further characterized in the CE part for next steps of clinical development. Key secondary objectives include the characterization of pharmacokinetics (PK) and efficacy assessment of SEL24/MEN1703 given as single agent; exploratory objectives include the assessment of relevant biomarkers (e.g. pS6) in peripheral blood and bone marrow, and their correlation with PK at different time points. Correlation of clinical activity and the cell surface antigen CD25 will be also explored. Study update Currently, the study is enrolling at 5 US sites and will be extended both in the US and EU. The recruitment started in March 2017 and, as of July 26th, 2019, 24 patients received SEL24/MEN1703 at dose levels ranging from 25 to 150 mg. Patients had a median age of 69 (25-84) years and a median of 3 (0-8) prior treatments for AML. Adverse prognostic factors such as primary refractory AML, unfavorable cytogenetics and prior MDS history accounted for 45.8%, 37.5%, 33.% of study patients, respectively. The most frequently reported mutations were FLT3-ITD (20.8% of patients) and those of DNMT3A and IDH1 (16.7% each). Conclusions This is the first trial testing a dual PIM/FLT3 inhibitor with the potential to overcome FLT3 inhibitor resistance, but also to be active in AML regardless of FLT3 mutational status. Ongoing adjustment of the DE design, including the switch to an optimized oral formulation, has been performed to obtain more robust data on the RP2D (ClinicalTrials.gov Identifier: NCT03008187). Disclosures Nazha: Incyte: Speakers Bureau; Tolero, Karyopharma: Honoraria; MEI: Other: Data monitoring Committee; Novartis: Speakers Bureau; Jazz Pharmacutical: Research Funding; Abbvie: Consultancy; Daiichi Sankyo: Consultancy. Strickland:Astellas Pharma: Consultancy; Sunesis Pharmaceuticals: Research Funding; AbbVie: Consultancy; Jazz: Consultancy; Kite: Consultancy; Pfizer: Consultancy. Walter:Boehringer Ingelheim: Consultancy; Agios: Consultancy; Amgen: Consultancy; Amphivena Therapeutics: Consultancy, Equity Ownership; Aptevo Therapeutics: Consultancy, Research Funding; Argenx BVBA: Consultancy; Astellas: Consultancy; BioLineRx: Consultancy; BiVictriX: Consultancy; Jazz Pharmaceuticals: Consultancy; Kite Pharma: Consultancy; New Link Genetics: Consultancy; Pfizer: Consultancy, Research Funding; Race Oncology: Consultancy; Seattle Genetics: Research Funding; Boston Biomedical: Consultancy; Covagen: Consultancy; Daiichi Sankyo: Consultancy. Valimberti:Menarini Ricerche S.p.A: Employment. Tagliavini:Menarini Ricerche S.p.A: Employment. Mazzei:Menarini Ricerche S.p.A.: Employment. Fiesoli:Menarini Ricerche S.p.A.: Employment. Scartoni:Menarini Ricerche S.p.A.: Employment. Bellarosa:Menarini Ricerche S.p.A.: Employment. Binaschi:Menarini Ricerche S.p.A.: Employment. Chrom:Selvita S.A.: Employment. Baldini:Menarini Ricerche S.p.A.: Employment. Brzózka:Selvita S.A.: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Capriati:Menarini Ricerche S.p.A.: Employment. Pellacani:Menarini Ricerche S.p.A.: Employment; Amgen: Equity Ownership. Ravandi:Macrogenix: Consultancy, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cyclacel LTD: Research Funding; Xencor: Consultancy, Research Funding; Menarini Ricerche: Research Funding; Selvita: Research Funding.

Phase 1-2 Study of Pembrolizumab Combined with the Anti-LAG-3 Antibody MK-4280 for the Treatment of Hematologic Malignancies

Phase 1-2 Study of Pembrolizumab Combined with the Anti-LAG-3 Antibody MK-4280 for the Treatment of Hematologic Malignancies

Safety, Clinical Activity, Pharmacokinetics, and Pharmacodynamics from a Phase I Study of PF-06863135, a B-Cell Maturation Antigen (BCMA)-CD3 Bispecific Antibody, in Patients with Relapsed/Refractory Multiple Myeloma (RRMM)

Introduction: PF-06863135 (PF-3135) is a bispecific, humanized, monoclonal antibody (mAb) consisting of BCMA- and CD3-targeting arms paired on an IgG2a backbone by hinge-mutation technology. PF-3135 binds BCMA+ myeloma cells and CD3+ T cells with affinities of 20 pM and ~40 nM, respectively (Panowski et al. Blood 2016). We report here findings from the dose-escalation portion of an ongoing, multi-center, open-label, phase I study (NCT03269136) of PF-3135 in patients with RRMM. Methods: Adult patients (≥18 years of age) with RRMM, previously treated with a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 mAb, received escalating, intravenous (IV) doses of PF-3135, once weekly. Prior BCMA-targeted bispecific T-cell engager or chimeric antigen receptor T-cell (CART) treatment was allowed by protocol. Patients had measurable disease per the International Myeloma Working Group (IMWG) updated criteria 2014. A modified toxicity probability interval method (mTPI), targeting a dose-limiting toxicity (DLT) rate of 25% (equivalence interval ± 5%) was used for dose escalation. The primary study objectives are to assess PF-3135 safety and tolerability, to determine the maximum tolerated dose (MTD) and select the recommended phase II dose (RP2D). Secondary objectives include evaluation of anti-myeloma activity, pharmacokinetics (PK), and immunogenicity of PF-3135. Results: As of April 9, 2019, 17 patients had received once weekly, non-continuous, IV infusion of PF-3135 in 6 dose-escalation groups. The majority were men (71%). The median age was 61 yrs (range, 47-82 yrs) and median disease duration since onset was 7 yrs (range, 1.1-13.3 yrs). Ten (59%) patients had ≥1 chromosomal abnormality and 5 (29%) had a normal karyotype (status not known for 2 [12%] patients). The median number of prior anti-myeloma therapies was 11; 5 (29%) patients had received prior BCMA-targeted therapy. Eight (47%) patients had relapsed MM and 8 (47%) had refractory disease (recurrence type not known for 1 [6%] patient). Ten (59%) patients experienced treatment-related (TR) AEs of any grade. Most TRAEs were grade 1-2, including cytokine release syndrome (CRS, 24%), thrombocytopenia (24%), anemia (18%), and pyrexia (18%). Three (18%) patients had grade 3 TRAEs (increased alanine aminotransferase/aspartate aminotransferase, leukocytopenia, neutropenia, and lymphopenia). One patient treated at the highest dose level, who had received prior BCMA CART therapy, developed treatment-related febrile neutropenia, a DLT, which may have been related to CRS and borderline/low neutrophil count at baseline. None of the patients had grade 4-5 TRAEs or discontinued treatment due to a TRAE. The median duration of treatment was 4 (range, 2-12) actual dosing days. Sixteen of the 17 patients were evaluable for response. At the time of data cut-off, one (6%) patient had a minimal response and 6 (35%) patients had stable disease (SD) across dose levels, as best response by investigator IMWG assessment; 9 (53%) patients experienced disease progression. The clinical benefit rate (defined as best response ≥SD) was 41% (95% CI: 18.4%, 67.1%). Conclusions: Treatment with IV PF-3135 was well tolerated at the dose levels evaluated. The observed CRS events were moderate and dose-dependent. Additional dose cohorts are accruing. The latest clinical, biomarker, and PK data will be presented for this ongoing study. Disclosures Raje: Medscape: Honoraria; Research to Practice: Honoraria; Takeda: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; AstraZeneca: Research Funding. Jakubowiak:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Consultancy, Honoraria; Juno: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; SkyLineDx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; KaryoPharm Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Gasparetto:Janssen: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; BMS: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; Celgene: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed . Cornell:KaryoPharm: Consultancy; Takeda: Consultancy. Krupka:Pfizer: Employment, Equity Ownership. Navarro:Pfizer: Employment, Equity Ownership. Forgie:Pfizer: Employment, Equity Ownership. Udata:Pfizer: Employment, Equity Ownership. Basu:Pfizer: Employment, Equity Ownership. Chou:Pfizer: Employment, Equity Ownership. Leung:Pfizer: Employment, Equity Ownership. Lesokhin:BMS: Consultancy, Honoraria, Research Funding; Serametrix Inc.: Patents & Royalties; Takeda: Consultancy, Honoraria; Genentech: Research Funding; Juno: Consultancy, Honoraria; GenMab: Consultancy, Honoraria; Janssen: Research Funding. OffLabel Disclosure: PF-06863135, investigational agent