Dose escalation and expansion from the phase I study of DS-1062, a trophoblast cell-surface antigen 2 (TROP2) antibody drug conjugate (ADC), in patients (pts) with advanced non-small cell lung cancer (NSCLC).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 9619-9619 ◽  
Author(s):  
Aaron Elliott Lisberg ◽  
Jacob Sands ◽  
Toshio Shimizu ◽  
Jonathan Greenberg ◽  
Penny Phillips ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Dose Escalation ◽  
Standard Treatment ◽  
Phase 1 ◽  
Human Study ◽  
Maximum Tolerated Dose ◽  
Dose Effect ◽  
Antibody Drug Conjugate ◽  
Grade 3 ◽  
Experienced Grade

9619 Background: TROP2 is an intracellular calcium signaling transducer overexpressed in NSCLC, portending poor survival. DS-1062 is a TROP2-targeting ADC with a novel topoisomerase 1 inhibitor (exatecan derivative, DXd) and promising preclinical antitumor activity. Updated results inclusive of 24 additional dose escalation pts and 32 dose expansion pts from an ongoing phase 1 study of DS-1062 in advanced/metastatic NSCLC are reported (NCT03401385/J101). Methods: Pts aged ≥18 (US) or ≥20 (Japan) with unresectable NSCLC refractory to/relapsed from standard treatment with measurable disease (RECIST v1.1) and available tumor for retrospective TROP2 evaluation were eligible. Primary objectives include maximum tolerated dose (MTD) identification, safety, and tolerability and secondary objectives include efficacy, pharmacokinetics, and incidence of anti-drug antibodies against DS-1062. Pts were eligible regardless of TROP2 level. Results: As of November 16, 2019, 95 pts were treated with ≥1 dose of DS-1062. 63 pts were treated during escalation at 0.27 (n = 4), 0.5 (n = 5), 1.0 (n = 7), 2.0 (n = 6), 4.0 (n = 6), 6.0 (n = 19), 8.0 (n = 8), and 10.0 (n = 8) mg/kg and 32 pts were treated in expansion at the MTD of DS-1062, 8 mg/kg. 59 pts (62%) discontinued (25 [42%] due to progressive disease per RECIST v1.1). Pts were exposed to a median of 3 treatment cycles (range, 1-19). In 88 response-evaluable pts, 22 had partial response (1 PR/6 pts at 2.0 mg/kg, 2 PR/6 pts at 4.0 mg/kg, 5 PR/18 pts at 6.0 mg/kg, 13 PR/34 pts at 8.0 mg/kg, and 1 PR/8 pts at 10.0 mg/kg; 14 PRs were confirmed and 8 PRs are awaiting confirmation). Treatment emergent adverse events (TEAEs) regardless of causality were reported in 91 of 95 pts (96%; 44 pts [46%] experienced ≥grade 3, 30 pts [32%] had serious events). Treatment-related TEAES were reported in 76 of 95 pts (80%; 17 pts [18%] experienced ≥grade 3, 8 pts [8%]) had serious events). Potential interstitial lung disease (ILD) occurred in 8 pts (8%; 2 at 6.0 mg/kg and 6 at 8.0 mg/kg); 6/8 with potential ILDs adjudicated as treatment-related (1 at 6.0 mg/kg [grade 2] and 5 at 8.0 mg/kg [1 grade 1, 2 grade 2, 1 grade 3, and 1 grade 5]). 14 escalation pts and 22 expansion pts remain on trial. Updated trial details/results will be presented. Conclusions: In this first-in-human study of DS-1062, treatment was well tolerated up to 8 mg/kg, and a dose effect on antitumor activity was observed over 2.0-10.0 mg/kg in heavily pretreated pts with prior progression on standard treatment. Clinical trial information: NCT03401385 .

Phase 1 study of infusional or bolus deflexifol (a novel formulation of 5FU, folinic acid, and cyclodextrin) after failure of standard treatment.

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. TPS812-TPS812
Author(s):  
Philip R. Clingan ◽  
Stephen P. Ackland ◽  
Marie Ranson ◽  
Paul De Souza ◽  
Ali Tafreshi ◽  
...  
Keyword(s):  
Anticancer Drugs ◽  
Dose Escalation ◽  
Standard Treatment ◽  
Phase 1 ◽  
Maximum Tolerated Dose ◽  
Clinical Activity ◽  
Dose Escalation Study ◽  
Advanced Malignancy ◽  
High Ph ◽  
Grade 3

TPS812 Background: 5FU is a commonly used anti-cancer agent first synthesized in 1957, and is now most commonly used in combination with FA, which enhances its clinical activity. Physical incompatibilities between 5FU and LV necessitate the infusion of each component separately, often through a central line due to high pH; resulting in adverse events, which leads to poor outcomes due to treatment interruption and discontinuation. A novel all in one reformulation of 5FU/LV at physiological pH has been developed as an alternative to serial administration of 5FU and LV in a high Ph solution [Locke JM, Anticancer Drugs 2009]. Preclinical testing demonstrated that the reformulation is stable bioequivalent to 5FU with reduced side effects [Stutchbury TK, Anticancer drugs 2011]. Methods: An open label phase 1 dose escalation study is underway in 2 schedules (bolus and infusion) to assess the safety and tolerability in patients with advanced malignancy after failure of standard treatment (including fluoropyrimidine regimens). To determine the maximum tolerated dose defined as: 2 out of 6 patients experience DLTs dose escalation is halted and declared DLT Dose. The previous dose level will be considered for expansion to x6 patients to confirm Maximum Tolerated Dose (MTD). Also to determine pharmacokinetic profile. Patients enrolled in Cohorts 1 to 4, have been completed without DLT. Dose-limiting toxicity (DLT) is defined as: Any Grade 3 or 4 non-haematologic toxicity (CTACE criteria). Patients developing Grade 3 or 4 diarrhoea, failing maximal anti-diarrheal medications. Febrile neutropenia, Grade 4 neutropenia > 7 days, Grade 4 thrombocytopenia > 7 days Any grade of thrombocytopenia associated with bleeding. Currently proceeding with (bolus 575mg/m2 weekly x 6, infusion 3600mg/m2/46h q2W). Limited sampling PK of 5-FU and dihydoFU is being conducted (3 at each of the 5 dose levels, doses 1 and 6). In both schedules to assess PK variability, adequacy of dosing in comparison to previous reports. The incidence of AEs and SAEs (CTACE 4.03) will be summarized by severity and relationship to study treatment. Clinical trial information: 044867.

Phase 1 dose escalation study of XMT-1536, a novel NaPi2b-targeting antibody-drug conjugate (ADC), in patients (pts) with solid tumors likely to express NaPi2b.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 3010-3010
Author(s):  
Anthony W. Tolcher ◽  
Susanna Varkey Ulahannan ◽  
Kyriakos P. Papadopoulos ◽  
William Jeffery Edenfield ◽  
Ursula A. Matulonis ◽  
...  
Keyword(s):  
Heart Failure ◽  
Congestive Heart Failure ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Phase 1 ◽  
Systemic Exposure ◽  
Maximum Tolerated Dose ◽  
Antibody Drug Conjugate ◽  
Dose Escalation Study ◽  
Grade 3

3010 Background: XMT-1536 is a Dolaflexin ADC targeting the sodium-phosphate cotransporter NaPi2b, expressed in ovarian, non-squamous lung, papillary thyroid, endometrial, papillary renal and salivary duct cancers. Methods: In this ongoing Phase 1 study, pts with solid tumors likely to express NaPi2b, who progressed on standard therapy, are treated with intravenous XMT-1536 using a 3+3 design with a modified Fibonacci escalation. NaPi2b expression by IHC is being examined retrospectively in archived tumors. Primary objectives in dose escalation are safety and tolerability and determination of maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D). (ClinicalTrials.gov NCT03319628). Results: As of Jan. 28, 2019, 36 pts (22 ovarian, 7 endometrial, 4 NSCLC, 3 other) have received treatment with XMT-1536. Treatment was initially given every 3 weeks (q3w); 20 pts were treated in dose cohorts from 3 to 40 mg/m2. There was one DLT of reversible AST elevation at 40 mg/m2. The dosing interval was then changed to every 4 weeks (q4w), and dose escalation was restarted at 20 mg/m2. There was one DLT of reversible AST elevation at 30 mg/m2 on the q4w schedule. Further followup and dose escalation are ongoing. The most common (≥10% of patients) treatment-related adverse events (TRAEs) have been nausea, fatigue, headache, increased AST, anorexia, increased alkaline phosphatase, fever, increased GGT, myalgia, and vomiting. Grade 3 TRAEs were reversible AST increases in 3 patients and increased GGT, decreased lymphocytes, and systolic congestive heart failure in 1 patient each. Treatment-related serious AEs of fever and systolic congestive heart failure occurred in 1 patient each. Among patients dosed at 20 mg/m2 or higher who had restaging scans (n=20), there were 2 PR, in ovarian cancer pts at 30 mg/m2 q3w and 20 mg/m2 q4w, and 11 SD, with disease control maintained for up to 24 weeks. Patient-level results for NaPi2b expression will be presented. The systemic exposure of total payload showed approximately dose-proportional increase. Plasma concentration of free drug payload and its active metabolite were low. Conclusions: XMT-1536 has been well-tolerated up to the 30 mg/m2 dose level with early signs of anti-tumor activity. Dose escalation continues in pts with advanced solid tumors likely to express NaPi2b. Clinical trial information: NCT03319628.

393 First-in-human phase 1/2a study of the novel nonfucosylated anti–CTLA-4 monoclonal antibody BMS-986218 ± nivolumab in advanced solid tumors: initial phase 1 results

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A418-A418
Author(s):  
Claire Friedman ◽  
Paolo Ascierto ◽  
Diwakar Davar ◽  
Mark O’Hara ◽  
Ronnie Shapira-Frommer ◽  
...  
Keyword(s):  
T Cell ◽  
Antitumor Activity ◽  
Advanced Cancer ◽  
Dose Escalation ◽  
Medical Center ◽  
Phase 1 ◽  
Maximum Tolerated Dose ◽  
Clinical Activity ◽  
List Type ◽  
Grade 3

BackgroundCTLA-4 pathway blockade with ipilimumab (IPI) ± nivolumab (NIVO; anti–PD-1) is an effective treatment for several cancers. A nonfucosylated version of IPI, BMS-986218, was developed to increase the effects of CTLA-4 blockade and enhance intratumoral regulatory T-cell depletion via its increased affinity for Fcγ receptors (FcγR, CD16) on natural killer T cells and macrophages, resulting in enhancement of antibody-dependent cellular cytotoxicity. Preclinical data supported the mechanism of action of BMS-986218 and demonstrated greater antitumor activity in an MC38 tumor model vs IPI.1 Here, we present initial results from the first-in-human phase 1/2a trial of BMS-986218 ± NIVO in previously treated patients with advanced cancer (NCT03110107).MethodsPatients with ≥1 prior therapy received BMS-986218 2–70 mg intravenously Q4W. Safety, tolerability, pharmacokinetics, and pharmacodynamics were evaluated.ResultsAs of December 12, 2019, 65 patients (median age, 61 years [range, 24–85 years]) received BMS-986218 monotherapy. TRAEs occurred in 52% of patients; most were grade 1–2. The most common (≥10%) TRAEs (any grade; grade 3) were pruritus (12%; 0%) and diarrhea (11%; 3%). Eight patients (12%) had grade 3 TRAEs; most resolved with protocol-defined management. No grade 4 TRAEs were reported; 1 grade 5 TRAE (pneumonitis; 2 mg) occurred. Seven patients (11%) discontinued treatment due to TRAEs; 4 dose-limiting toxicities occurred. The maximum tolerated dose has not been reached. BMS-986218 exposure increased dose proportionally, and the half-life was ≈2 weeks. Increased levels of serum chemokine ligands 9 and 10 and interferon-γ indicate that pharmacodynamic changes occurred at the lowest dose tested (2 mg [≈0.03 mg/kg]), similar to previous findings with IPI 3 mg/kg, and at higher doses (40–70 mg [≈0.06–1 mg/kg]), consistent with findings with IPI 10 mg/kg. In a subset of patients with paired biopsies, BMS-986218 was associated with an increased gene signature linked to CD8+ T-cell infiltration and inflammation. In a highly heterogeneous population, as part of dose escalation, BMS-986218 monotherapy treatment was associated with clinical activity in some patients. Updated data based on a September 2020 data cutoff will be presented.ConclusionsBMS-986218 monotherapy demonstrated an acceptable safety profile and signs of clinical benefit in this heterogeneous patient population with select advanced cancers. Preliminary pharmacodynamic activity was consistent with enhanced effects of CTLA-4 blockade. Data from continuing dose escalation of BMS-986218 ± NIVO along with preclinical results provide support for ongoing monotherapy expansions and for BMS-986218 + NIVO expansions in patients with advanced cancer.AcknowledgementsThe authors acknowledge Dr Charles Drake while at Columbia University Medical Center, New York, NY, USA, for his contributions to the study.Trial RegistrationNCT03110107Ethics ApprovalThis study was approved by the WCG Independent Review Board, approval number 20170464ReferenceEngelhardt J, Akter R, Valle J, et al. Preclinical characterization of BMS-986218, a novel nonfucosylated anti–CTLA-4 antibody designed to enhance antitumor activity. Presented at the American Association for Cancer Research (AACR) Virtual Annual Meeting II; June 22–24, 2020 [poster 4552].

An open-label study of rovalpituzumab tesirine in patients with DLL3-expressing advanced solid tumors.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS2597-TPS2597 ◽  
Author(s):  
Edward Kavalerchik ◽  
Satwant Lally ◽  
Tae H. Han ◽  
Laura R. Saunders ◽  
Sheila Bheddah ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Dose Escalation ◽  
Solid Tumor ◽  
Phase 1 ◽  
Large Cell ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Notch Receptor ◽  
Antibody Drug Conjugate ◽  
Open Label

TPS2597 Background: Delta-like protein 3 (DLL3) is an inhibitory ligand of the Notch receptor family. It is highly expressed in high-grade neuroendocrine carcinoma (NEC), such as small cell lung cancer (SCLC) and large cell NEC (LCNEC), but is not expressed in normal tissue. DLL3 is expressed in melanoma, glioblastoma (GBM), neuroendocrine prostate, medullary thyroid carcinoma (MTC), and other solid cancers. Rovalpituzumab tesirine (Rova-T™) is an antibody-drug conjugate targeting DLL3, composed of a DLL3-specific IgG1 monoclonal antibody joined to a toxic DNA cross-linking agent by a cleavable linker. Rova-T binds to DLL3 on target-expressing cells, is internalized and cleaved, releasing the toxin to induce cell death. A Phase 1 study of Rova-T in SCLC showed encouraging antitumor activity in DLL3-high patients (pts), and was well-tolerated (Rudin et al., Lancet Oncol, 2016). As novel therapies are needed for multiple cancers that express DLL3, Rova-T may be effective in these tumors. Methods: This is a Phase 1/2, open-label, multicenter study (NCT02709889) with 8 cohorts of pts (up to ~318 total, 14 pts enrolled as of 20 January 2017) with melanoma, MTC, GBM, LCNEC, neuroendocrine prostate cancer, gastroenteropancreatic NEC, other NEC, or other solid tumor. In Part A, a 3+3 dose escalation will be used. Rova-T 0.2, 0.3, or 0.4 mg/kg will be given on Day 1 of each 42-day cycle. Dose-limiting toxicities (DLTs) will be assessed over a 21-day period. Dose escalation will proceed within cohort until a maximum tolerated dose is reached. Part B expansion, Stage 1, will explore the recommended dose in 7 pts in disease specific cohorts. Stage 2 will use an adaptive 2-stage design to determine sample size. Pt eligibility: ≥ 18 years; histologically confirmed, measurable, advanced solid tumor; relapsed/refractory to prior standard therapy; ECOG 0-1; no prior exposure to a pyrrolobenzodiazepine-based drug. Primary objective: assess safety and tolerability of Rova-T. Secondary objectives: explore Rova-T antitumor activity, pharmacokinetics, and incidence of anti-therapeutic antibodies. Exploratory objectives: explore the relationship between DLL3 and clinical outcome, and effects on biomarkers and pharmacodynamics. Clinical trial information: NCT02709889.

2-Chlorodeoxyadenosine dose escalation in nonhematologic malignancies.

1993 ◽  
Vol 11 (4) ◽  
pp. 671-678 ◽  
Author(s):  
A Saven ◽  
H Kawasaki ◽  
C J Carrera ◽  
T Waltz ◽  
B Copeland ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Intravenous Infusion ◽  
Hematologic Malignancies ◽  
Maximum Tolerated Dose ◽  
Malignant Astrocytoma ◽  
Dose Escalation Study ◽  
Tissue Samples ◽  
Grade 3 ◽  
Higher Doses ◽  
Experienced Grade

PURPOSE We performed a dose-escalation study of 2-chlorodeoxyadenosine (2-CdA) in solid tumors to determine the maximum-tolerated dose (MTD) and define its toxicity profile at higher doses. PATIENTS AND METHODS Twenty-one patients, seven with malignant astrocytoma, twelve with metastatic melanoma, and two with metastatic hypernephroma, were enrolled onto the study. Patients were entered onto cohorts that received 0.10, 0.15, or 0.20 mg/kg/d of 2-CdA by continuous intravenous infusion for 7 days every 28 days. 2-CdA levels were determined by radioimmunoassay. In tumor tissue samples, deoxycytidine kinase (dCK) levels were measured by both enzyme activity and immunoreactive protein analysis. RESULTS Of seven patients treated with 2-CdA at 0.1 mg/kg/d, one experienced grade 3 or 4 myelotoxicity. Of 11 patients treated at 0.15 mg/kg/d, four experienced myelotoxicity, two after a single course of 2-CdA. All three patients who received 2-CdA at 0.2 mg/kg/d experienced myelosuppression. Neurologic events occurred in two patients, both with malignant melanoma. Two of seven patients (28.6%) with astrocytomas obtained partial responses with a median duration of 8 months. 2-CdA penetrated the blood-brain barrier. An association was found between dCK levels as measured by enzymatic activity and immunoreactive proteins, but this did not correlate with 2-CdA tumor responsiveness. CONCLUSION The MTD for 2-CdA delivered as a 7-day intravenous infusion in patients with nonhematologic malignancies was determined to be 0.1 mg/kg/d, the same as the MTD for patients with hematologic malignancies. There was no clinical correlation with dCK expression and response to 2-CdA. The responses noted in patients with malignant astrocytoma warrant further phase II study.

Banoxantrone (AQ4N), a Tissue Targeted Prodrug: Results of a Phase 1 Study in Lymphomas.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2429-2429
Author(s):  
Richard R. Furman ◽  
Nancy L. Bartlett ◽  
Alvin F. Wong ◽  
Leanne M. McCulloch ◽  
Gilbert N. Lam ◽  
...  
Keyword(s):  
Partial Response ◽  
Follicular Lymphoma ◽  
Dose Escalation ◽  
Clinical Studies ◽  
Topoisomerase Ii ◽  
Phase 1 ◽  
Maximum Tolerated Dose ◽  
Blood Levels ◽  
Dna Intercalator ◽  
Grade 3

Abstract AQ4N is a prodrug which is selectively bioreduced by cytochrome P450 to AQ4, a potent DNA intercalator and topoisomerase II inhibitor. Preclinical studies demonstrate AQ4N selectively targets lymphoblastoid cell lines and hypoxic tumors. This study assessed the maximum tolerated dose (MTD), and pharmacokinetics (PK) of repeated dosing of AQ4N in patients (pts) with lymphoid malignancies. AQ4N was administered IV on Day 1 of a 21 day cycle to cohorts of at least three pts at doses of 400, 800, or 1200 mg/m2 for a maximum of 8 cycles. The dose was escalated as long as <33% of pts did not experience a dose limiting toxicity (DLT). 11 pts were enrolled with 3 pts treated at 400 mg/m2 and 4 pts treated at 800 and 1200 mg/m2 each. No pts experienced a DLT and no clinical MTD was identified. No further dose escalation was investigated due to reaching known maximum AQ4N solution solubility. The most common related adverse events (AE) observed were expected transient skin discoloration (100%), transient chromaturia (36%) and lymphopenia (27%), as well as fatigue (27%) and nausea (27%). AEs were primarily mild (Grade 1–2) with the exception of Grade 3 lymphopenias (n=3) and Grade 3 neutopenia (n=1) events. No dose reductions or dose delays resulted from these hematologic decreases. 6 pts experienced at least one serious AE, including: pneumonia, staph aureus bacteremia, acute respiratory distress syndrome (ARDS), dyspnea, and pleural effusion, none of which were attributed to AQ4N. The PK was linear over all doses studied. At 1200 mg/m2 (n=4), the Day 1 AQ4N Cmax was 122.3 ± 13.1 μg/mL, AUC0–∞ was 340.8 ± 68.7 μg·h/mL, and T1/2 was 3.2 h (range 2.8 to 4.1 h). One pt with follicular lymphoma dosed at 1200 mg/m2 had a partial response after the 4th cycle using the NHL standardized response criteria. The pt went on to complete all 8 cycles and to date remains in partial response. The bioreductive prodrug, AQ4N, is well-tolerated when administered on a repeated 21-day schedule at doses up to and including 1200 mg/m2. Further dose escalation was precluded since the known maximum solubility of AQ4N was reached. Blood levels of AQ4N achieved in this study appear to be within the range of potentially therapeutic levels of the active drug, AQ4, as seen in previous preclinical and clinical studies of solid tumors (Harris PA et al, 2006; Albertella MR et al., 2006). Preliminary evidence of anti-tumor activity was seen in one pt with follicular lymphoma. Further clinical studies of AQ4N administered both as a monotherapy and in combination with chemo- and radiation therapy are planned in B-cell neoplasms and solid tumor malignancies.

Phase 1 dose escalation study of MEDI-565, a bispecific T-cell engager that targets human carcinoembryonic antigen (CEA), in patients with advanced gastrointestinal (GI) adenocarcinomas.

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 320-320
Author(s):  
Michael J. Pishvaian ◽  
Michael Morse ◽  
Jennifer T. McDevitt ◽  
Song Ren ◽  
Gabriel Robbie ◽  
...  
Keyword(s):  
T Cell ◽  
Antitumor Activity ◽  
Dose Escalation ◽  
Half Life ◽  
High Titer ◽  
Phase 1 ◽  
Single Chain ◽  
Dose Escalation Study ◽  
Human T Cell ◽  
Grade 3

320 Background: MEDI-565, a bispecific single-chain antibody, targets human CEA on tumor cells and the CD3 epsilon subunit of the human T-cell receptor complex. In murine models, MEDI-565 showed antitumor activity in CEA-expressing tumors (J Immunother 2009;34:341-52). Methods: This phase 1, multicenter, open-label, dose-escalation study enrolled adults with GI adenocarcinomas (including esophageal, gastric, small intestine, colorectal, biliary tract, and pancreatic). MEDI-565 was given intravenously over 3 h on days 1–5 in 28-day cycles, with 4 single-patient (pt) (0.75–20 μg) and 5 standard 3+3 escalation (60 μg–3 mg; 1.5–7.5 mg with dexamethasone [dex]) cohorts. Primary objective was to determine the maximum tolerated dose (MTD); secondary objectives were to evaluate pharmacokinetics (PK), antidrug antibody (ADA), and antitumor activity. Results: Study enrolled39 pts: mean age 59 y; 56% male; 28 (72%) colorectal, 6 (15%) pancreatic, 5 (13%) other. Dose-limiting toxicities (grade ≥ 3 nonhematologic) were seen in 4 pts (2 at 3-mg; 2 at 7.5-mg + dex): hypoxia (n = 2), diarrhea, and cytokine release syndrome (CRS). Grade 3 treatment-related adverse events (AEs) seen in 5 pts: diarrhea, CRS, increased alanine aminotransferase, hypertension (all n = 1), and hypoxia (n = 2). Treatment-related serious AEs seen in 6 pts: diarrhea, vomiting, pyrexia, CRS (all n = 1), and hypoxia (n = 2). Five pts discontinued treatment due to AEs: diarrhea, CRS, central nervous system metastases, and hypoxia (n = 2). MEDI-565 exposures increased in approximately dose-proportional manner, with clearance (35–77 L/d) and half-life (2–7 h) typical of drug class. ADA had minor impact; 19 pts (48.7%) had ADAs, 5/39 (12.8%) with high titer, with decreased MEDI-565 concentrations in 2 pts. Plasma inflammatory cytokines were elevated posttreatment in several pts at 1.5- and 3-mg (no dex) dose levels. No objective responses were observed; 11 (28%) pts had stable disease as best response. Conclusions: The MTD of MEDI-565 in pts with GI adenocarcinomas was 5 mg with dex. PK was linear, with fast clearance and short half-life. No objective responses were observed. Clinical trial information: NCT01284231.

A dose escalation phase 1 study of radiotherapy (RT) in combination with anti-cytotoxic-T-lymphocyte-associated antigen 4 (CTLA-4) monoclonal antibody ipilimumab in patients (pts) with metastatic melanoma.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 9549-9549 ◽  
Author(s):  
Celine Boutros ◽  
Christine Mateus ◽  
Emilie Lanoy ◽  
Emilie Routier ◽  
Salem Chouaib ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Metastatic Melanoma ◽  
Dose Escalation ◽  
Phase 1 ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Tumor Control ◽  
Severe Toxicity ◽  
Phase 1 Study ◽  
Grade 3

9549 Background: Preclinical findings have shown a synergy between RT and anti-CTLA-4 monoclonal antibody in several tumor animal models for both local tumor control and distant effects. Preliminary clinical data suggest that it could be due to an abscopal effect of RT. The Mel-Ipi-Rx phase 1 study aimed to determine the maximum tolerated dose (MTD) and safety profile of RT combined with ipilimumab in pts with metastatic melanoma. Methods: A 3+3 dose escalation design was used with 9, 15, 18 and 24 Gy dose of RT (in 3 fractions) at week 4 combined with 10 mg/kg ipilimumab (every 3 weeks for 4 doses). Pts with evidence of clinical benefit at week 12 were eligible for maintenance ipilimumab at 10 mg/kg every 12 weeks starting at week 24 until severe toxicity or disease progression based on immune-related response criteria (irRC). Results: 19 pts with advanced melanoma received ipilimumab between August 2011 and July 2015. Nine pts received the 4 doses of ipilimumab and 2 pts received maintenance ipilimumab (1 and 2 cycles respectively). All pts received the combined RT at week 4 in 3 fractions. All pts presented at least one AE of any grade. The most common AEs were asthenia, diarrhea, desease-related pain and fever. Grade 3 AEs occurred in 8 pts. They included colitis (n = 3), hepatitis (n = 2), anemia (n = 2), asthenia (n = 1), thyroid disorders (n = 1) and nausea/vomiting (n = 1). Nine pts discontinued the study owing to treatment-related adverse events including colitis (n = 6), hepatitis (n = 2) and DRESS (Drug Rash with Eosinophilia and systemic syndrome) (n = 1). DLT occurred in 2/6 pts in the cohort receiving 15 Gy. No drug-related death occurred. According to irRC, 4 partial responses (ORR: 21%) and 4 stable diseases were observed at week 24. The MTD was 9 Gy dose. One pt out of 12 treated in the 9 Gy cohort presented a DLT (grade 3 colitis). The median progression-free survival [95% CI] was 7.2 months [2.4 – 16.8]. The median overall survival [95% CI] was 14.4 months [7.2 – 20.4]. Conclusions: When combined with ipilimumab at 10 mg/kg, in the present design, the MTD of RT was 9 Gy. This combination appears to be associated with antitumor activity. Clinical trial information: 2010-020317-93.

CX-2009, a CD166-directed probody drug conjugate (PDC): Results from the first-in-human study in patients (Pts) with advanced cancer including breast cancer (BC).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 526-526
Author(s):  
Valentina Boni ◽  
Howard A. Burris III ◽  
Joyce F. Liu ◽  
Alexander I. Spira ◽  
Hendrik-Tobias Arkenau ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Advanced Cancer ◽  
Phase Ii ◽  
Dose Escalation ◽  
Human Study ◽  
Population Pharmacokinetic ◽  
Antibody Drug Conjugate ◽  
Dose Escalation Study ◽  
Drug Conjugate ◽  
Grade 3

526 Background: CX-2009 is a PROBODY drug conjugate (PDC) directed against CD166 (ALCAM) and conjugated to DM4, a potent microtubule inhibitor (MTI). CD166 is overexpressed in carcinomas but is also ubiquitously expressed in normal epithelium and thus has not been previously considered a viable target for a traditional antibody drug conjugate. PDCs have a peptide mask that blocks normal tissue binding and can be removed by tumor-associated proteases, thereby limiting off-tumor/on-target binding. CX-2009 demonstrated preclinical activity in multiple solid tumor models. Here we report results of the first in human study in patients with advanced cancer. Methods: In this phase I multi-part dose-escalation study, pts with advanced solid tumors received CX-2009 0.25–10 mpk IV every 14 or 21 days (Q2W or Q3W). Tumor types were selected based on expected high CD166 expression and MTI sensitivity. Results: The dose-escalation phase of the trial enrolled 43 pts; 49 additional pts were subsequently enrolled between 4–10 mpk to collect biomarker data and define the recommended phase II dose (RP2D), for a total of 92 pts as of 30 Nov 2019 (39 pts with breast cancer [BC], 22 ovarian [OC], 12 non-small cell lung [NSCLC], 9 head/neck squamous cell [HNSCC], 10 other) with a median of 6 (range 1–19) prior therapies. Median number of CX-2009 doses was 2 (range, 1–15). For Q3W dosing, one dose limiting toxicity (DLT; grade 3 vomiting) was observed at 8 mpk; MTD was not reached up to 10 mpk. The RP2D for Q3W schedule was 7 mpk based on safety, dose-response, and population pharmacokinetic simulations. Q2W dosing continues; DLTs were observed at 6 mpk. Common treatment-related adverse events (TRAEs) at 7 mpk (n=9) were nausea (44%), fatigue, infusion-related reactions (both 33%), vomiting and arthralgias (both 22%). Grade 3 TRAEs occurred in 2 pts (nausea/vomiting; peripheral neuropathy). No pts discontinued at 7 mpk due to TRAEs. Ocular toxicity was dose dependent; mild to moderate reversible keratitis/blurred vision was seen in 3 pts at 7 mpk and mitigated by ocular prophylaxis. Partial responses were seen in 8 pts (2 confirmed, both HR+/HER2- BC) treated between 4–10 mpk, including BC (n=5), OC (n=2), and HNSCC (n=1). SD (≥1 on-study scan) was observed in 21 pts, 5 had SD ≥3 mos. Conclusions: CX-2009 at 7 mpk is the RP2D on Q3W schedule. Phase II expansion has begun in pts with HR+/HER2- BC. The Q2W schedule will continue to enroll pts to define the RP2D. CX-2009 will also be studied in combination with CX-072, a PD-L1 PROBODY therapeutic ( NCT03149549 ) Clinical trial information: NCT03149549 .

First-in-human study of palcitoclax (APG-1252), a novel dual Bcl-2/Bcl-xL inhibitor, demonstrated advantages in platelet safety while maintaining anticancer effect in U.S. patients with metastatic solid tumors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3509-3509
Author(s):  
Nehal J. Lakhani ◽  
Drew W. Rasco ◽  
Qi Zeng ◽  
Yuefen Tang ◽  
ZHIYAN LIANG ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Phase 1 ◽  
Human Study ◽  
Maximum Tolerated Dose ◽  
Neuroendocrine Prostate Cancer ◽  
Important Approach ◽  
Expansion Stage ◽  
Further Development ◽  
Clinical Trial Information

3509 Background: Targeting Bcl-2/Bcl-xL proteins is considered as an important approach for anticancer drug development. Palcitoclax (APG-1252) was being developed to reduce on-target platelet toxicity without diminishing antitumor potency. Methods: The phase 1 study was to evaluate the safety/tolerability, pharmacokinetics (PK), and preliminary efficacy (assessed per RECIST 1.1) of palcitoclax in US patients with metastatic small-cell lung cancer (SCLC) or other solid tumors (NCT03080311). A standard “3+3” design was applied to the dose-escalation stage. Palcitoclax was administered IV infusion for 30 minutes, twice a week (BIW) or once a week (QW) for 3 weeks in a 28-day cycle. Once the maximum tolerated dose / recommended phase 2 dose (MTD/RP2D) was determined, additional patients were treated in a dose-expansion stage. Results: The dose-escalation phase has been completed with 42 patients (31 on BIW and 11 on QW) who received palcitoclax at 8 dose cohorts ranging 10 mg - 400 mg. Most adverse events (AEs) were grade 1 or 2 (G1 or G2), and 26.2% patients had ≥ G3 TRAEs. The most common TRAEs were platelet count decreased (14.3%), aspartate aminotransferase increased (9.5%), and alanine aminotransferase increased (7.1%). Rapid platelet drop was observed in patients treated at 320 mg and 400 mg, which was transient and resolved rapidly within 2-6 days. Palcitoclax at 240 mg once weekly was determined to be MTD/RP2D. Of 36 efficacy-evaluable patients, 3 patients with SCLC, neuroendocrine prostate cancer, and ovarian cancer respectively achieved partial response (PR) and 8 patients had stable disease (SD) as their best overall response. One patient with SCLC had a PR that lasted over 21 cycles. Preliminary PK analyses showed that Cmax and AUC were approximately dose proportional over the range of 10 mg to 320 mg following the IV infusion on Day 1, with a mean T1/2 of 3.0-13.0 hours. Conclusions: Palcitoclax is safe and well tolerated, with a favorable platelet toxicity profile. Its promising antitumor effect supports its further development in combination therapies for treatment of patients with SCLC and other solid tumors. Clinical trial information: NCT03080311 .

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