Phase 1b/2 trial of ribociclib+binimetinib in metastatic NRAS-mutant melanoma: Safety, efficacy, and recommended phase 2 dose (RP2D).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 9519-9519 ◽  
Author(s):  
Martin H. Schuler ◽  
Paolo A. Ascierto ◽  
Filip Yves Francine Leon De Vos ◽  
Michael Andrew Postow ◽  
Carla M.L.- Van Herpen ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Mapk Pathway ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Genetic Alterations ◽  
Primary Objective ◽  
Cell Cycle Checkpoint ◽  
Phase 2 ◽  
Phase 1B ◽  
Ecog Ps

9519 Background: Simultaneous inhibition of MEK and CDK4/6 may suppress MAPK pathway activation and cell-cycle checkpoint dysregulation in NRAS-mutant melanoma, resulting in enhanced antitumor activity. Phase 1b data are reported. Methods: The phase 1b primary objective was to determine maximum tolerated dose (MTD)/RP2D. A 28-d cycle of oral ribociclib (RIBO) once daily (QD) for 21 d + oral binimetinib (BINI) twice daily (BID) for 28 d, and a 21-d cycle of RIBO QD + BINI BID, both for 14 d per cycle, were evaluated. Secondary objectives were to evaluate efficacy, safety and pharmacodynamics. Results: Based on dose escalation (van Herpen, ESMO 2015), MTD was 600mg RIBO/45mg BINI for the 21-d and 200/45 for the 28-d regimens. Due to promising activity, the 28-d cycle was selected as RP2D(unconfirmed partial response [PR] with limited follow-up occurred in 35% of pts). This finding was supported by comparable and manageable safety and the Bayesian logistic regression model.As of Jan 2017, the RP2D was received by 16 pts in phase 1b (ECOG PS 0/1/2, 63%/31%/6%; elevated lactate dehydrogenase, 44%; stage IVM1c disease, 50%; prior ipilimumab [ipi], 44%; prior anti–programmed death [PD]-1/PD-L1, 31%). Median (range) exposure was 4 (0–13) mo. Common adverse events (AEs) were increased blood creatine phosphokinase, elevated AST, peripheral edema, acneiform dermatitis, diarrhea and fatigue. Common grade 3/4 AEs were elevated AST and ALT (19%/6%), nausea (19%/0%), rash (19%/0%), vomiting (6%/6%) and neutropenia (12%/0%). Confirmed PR (cPR) occurred in 4 pts (25%; time to response, 48–168 d), stable disease in 7 pts (44%), disease progression in 3 pts (19%); 2 pts (12%) were not evaluable. Among cPR pts, 3 had prior ipi and/or anti–PD-1/PD-L1. Median progression-free survival (mPFS) was 6.7 (95% CI, 3.5–9.2) mo. Sequence analysis of synchronous non- RAS genetic alterations will be presented. Conclusions: Combined RIBO/BINI at the selected RP2D had a manageable safety profile and favorable efficacy (based on mPFS) for NRAS-mutant melanoma in phase 1b. Based on these promising data, the phase 2 expansion is underway to assess antitumor activity at the RP2D. Clinical trial information: NCT01781572.

A multicenter, randomized phase 1b/2 study of gemcitabine and cisplatin with or without CPI-613 as first-line therapy for patients with advanced unresectable biliary tract cancer (BilT-04).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS4158-TPS4158
Author(s):  
Vaibhav Sahai ◽  
Amy E. Chang ◽  
Oxana V. Crysler ◽  
David Bing Zhen ◽  
Muhammad Shaalan Beg ◽  
...  
Keyword(s):  
Overall Survival ◽  
Biliary Tract ◽  
Alternative Hypothesis ◽  
Progression Free Survival ◽  
Primary Objective ◽  
Phase 2 ◽  
First Line ◽  
Eligibility Criteria ◽  
Phase 1B ◽  
Gemcitabine And Cisplatin

TPS4158 Background: Patients (pts) with advanced biliary tract cancers (BTC) have poor prognosis despite systemic chemotherapy. Gemcitabine and cisplatin is a standard first-line systemic therapy with an overall response rate (ORR) of 26% and a median overall survival of 11.7 months. This investigator-initiated, multi-institutional phase 1b/2 trial is designed to investigate the role of gemcitabine, cisplatin and CPI-613 in pts with advanced BTC. CPI-613 is a stable intermediate of a lipoate analog that inhibits pyruvate dehydrogenase and a-ketoglutarate dehydrogenase enzymes of the tricarboxylic (TCA) cycle preferentially within the mitochondria of cancer cells. Methods: Key eligibility criteria include histologically confirmed, metastatic or unresectable BTC (intra- or extra-hepatic and gallbladder) without prior systemic treatment, measurable disease per RECIST v1.1, and ECOG PS 0-1. Primary objective of the phase 1b portion (n = 20 pts; TiTE-CRM methodology) is to determine the recommended phase 2 dose of the combination, and for the phase 2 portion, ORR (n = 48-58 pts; 2:1 randomization). Assuming a null hypothesis ORR of 25% and an alternative hypothesis of 43%, this ongoing trial has at least 80% power with a one-sided alpha of 0.05 to identify treatment efficacy of the study arm. Secondary objectives include evaluation of progression-free survival, overall survival, and safety in this patient population. Exploratory objectives include identification of molecular markers of response and resistance in tumor samples and serially collected blood (pre-, on-, and post-therapy), including whole exome/transcriptomic analysis, and immunohistochemical staining (PDK, PDH, KGDH, SOD2 and CD79a). Gemcitabine 1000 mg/m2, cisplatin 25 mg/m2 with or without CPI-613 (dose levels: 500 mg/m2, 1000 mg/m2, 1500 mg/m2, and 2000 mg/m2) will be given IV on days 1 and 8 every 21 days. In the absence of disease progression, pts may continue therapy for up to 2 years. Total accrual goal is 68-78 evaluable pts. To date, 5 of planned 20 pts enrolled on the phase 1b portion are without dose limiting toxicity. Clinical trial information: NCT04203160.

A phase I dose-escalation of trifluridine/tipiracil in combination with oxaliplatin in metastatic colorectal cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS3626-TPS3626 ◽  
Author(s):  
Antoine Hollebecque ◽  
Guillem Argiles ◽  
Thierry Andre ◽  
Andres Cervantes ◽  
Catherine Leger ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Antitumor Activity ◽  
Metastatic Colorectal Cancer ◽  
Dose Escalation ◽  
Phase 1 ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Dose Escalation Study ◽  
Nude Mouse Model

TPS3626 Background: Trifluridine/tipiracil, also known as TAS‐102, is a combination of an antineoplastic thymidine‐based nucleoside analogue (trifluridine) and a thymidine phosphorylase inhibitor (tipiracil hydrochloride). The antitumor activity of combined trifluridine/tipiracil and oxaliplatin has been studied in gastrointestinal tumor xenografts, including a 5‐FU resistant subline, using a nude mouse model. This study demonstrated increased antitumor activity for the combination compared to trifluridine/tipiracil or oxaliplatin alone (p < 0.001) (Nukatsuka et al., Anticancer Res 2015). These data support the rationale for clinical use of the combination. We describe a phase 1, international, dose-escalation study of the combination in metastatic colorectal cancer (mCRC). Methods: This trial includes mCRC patients pretreated with at least one line of standard chemotherapy. The 14‐day administration schedule of trifluridine/tipiracil differs from current clinical practice to avoid overlapping toxicity, notably decreased neutrophils due to oxaliplatin or trifluridine/tipiracil. Trifluridine/tipiracil is administered orally (cohort 1: 25 mg/m² bid; cohort 2: 30 mg/m² bid; cohort 3: 35 mg/m² bid) from day 1 to 5; and oxaliplatin at 85 mg/m² (with a possibility to reduce to 65 mg/m²) on day 1. The primary objective is to determine the maximum tolerated dose (MTD) through a 3+3 design. Secondary objectives include safety, pharmacokinetics, and preliminary efficacy (overall survival, progression‐free survival, overall response rate and biomarkers). As of December 2016, no dose‐limiting toxicities had been reported in cohorts 1 or 2. The MTD has not yet been reached and dose‐escalation continues with enrollment in cohort 3 at full dose for both drugs (trifluridine/tipiracil 35 mg/m² bid and oxaliplatin 85 mg/m²). Once established, the MTD will be confirmed in 6 additional patients to define the recommended dose to be used in the expansion part of the study planned in the same patient population. The results of the dose‐escalation part are expected in 2017. (NCT02848443). Clinical trial information: NCT02848443.

Phase 1b/2 study of enzalutamide (ENZ) with LY3023414 (LY) or placebo (PL) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) after progression on abiraterone.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 5009-5009 ◽  
Author(s):  
Christopher Sweeney ◽  
Ivor John Percent ◽  
Sunil Babu ◽  
Jennifer Cultrera ◽  
Bryan Allyn Mehlhaff ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Phase 1 ◽  
Single Agent ◽  
Progression Free Survival ◽  
Primary Objective ◽  
P Value ◽  
Phase 2 ◽  
Castration Resistant Prostate Cancer ◽  
Double Blind ◽  
Phase 1B

5009 Background: Preclinical and phase 1 results suggest PI3K/mTOR pathway inhibition may enhance androgen receptor inhibition. We report the results of a double-blind, placebo-controlled, randomized Phase 1b/2 study of ENZ±LY (a dual PI3K/mTOR inhibitor) in pts with mCRPC who progressed on abiraterone. Methods: Phase 1b pts received single-agent LY 200 mg twice daily (BID) for 1 wk prior to starting LY+ENZ. Phase 2 pts were randomized 1:1 to 160 mg daily ENZ with PL or 200 mg BID LY on a 28-d cycle. The primary objective was progression-free survival (PFS: serological, radiographic [rPFS], or death) by PCWG2 criteria. Secondary objectives were rPFS, safety, decline in PSA, and PK. Exploratory biomarker analyses included outcomes by presence of androgen receptor variant 7 (AR-V7). 92 primary PFS events were needed for the study to have at least 80% power at one-sided alpha=0.20. Results: LY+ENZ was tolerable during Phase 1b with 1 dose limiting toxicity observed in 13 enrolled pts. Mean LY exposures remained in an efficacious range despite a 30% average decrease when combined with ENZ. In Phase 2, 129 pts were randomized to LY+ENZ (N=65) and PL+ENZ (N=64) (Table). Median PCWG2-PFS was 3.7 mos (LY+ENZ) vs 2.9 mos (PL+ENZ) (HR 0.66, 95% CI 0.43, 0.99; p-value 0.0208). Conclusions: Combination LY+ENZ had a clinically manageable safety profile. The primary end-point of PCWG2-PFS was met and is supported by a clinically meaningful delay in rPFS in AR-V7 negative pts. The biomarker data provide important insights to inform future development strategies. Clinical trial information: NCT02407054. [Table: see text]

scholarly journals CTNI-45. A PHASE 1B/2 CLINICAL STUDY OF NAPABUCASIN IN COMBINATION WITH TEMOZOLOMIDE FOR ADULT PATIENTS WITH RECURRENT OR PROGRESSED GLIOBLASTOMA MULTIFORME (GBM)

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii52-ii52
Author(s):  
Andrew Chi ◽  
Paula DeRobles ◽  
Emma Foos ◽  
Matthew Hitron ◽  
Warren Mason
Keyword(s):  
Antitumor Activity ◽  
Objective Response ◽  
Dose Intensity ◽  
Progression Free Survival ◽  
Phase 2 ◽  
Open Label ◽  
Antitumor Effects ◽  
Patient Reported ◽  
Phase 1B ◽  
Grade 3

Abstract Napabucasin is an orally-administered NQO1–bioactivatable investigational agent hypothesized to affect multiple oncogenic cellular pathways including STAT3. This open-label, multicenter, phase 1b/2 study assessed napabucasin plus temozolomide for recurrent/progressive GBM. Phase 1b objectives were safety/tolerability, recommended phase 2 dose (primary), preliminary antitumor activity, and pharmacokinetics/pharmacodynamics (secondary). Phase 2 objectives were preliminary antitumor activity via 6-month progression-free survival (PFS-6 [20% projected]) (primary); disease control rate; median PFS; objective response rate (ORR); and overall survival (OS) (secondary). Arm A enrolled repeat surgical resection candidates; arm B enrolled patients ineligible for further resection. Patients received napabucasin (oral, 480 mg twice-daily) plus temozolomide (150 mg/m2, days 1–5, 28-day cycles). Arm A closed after 4 patients enrolled to prioritize Arm B enrollment. Arm B data are reported. Arm B enrolled/treated 30 patients (median age=56.5 [range=19–83] years; median napabucasin duration=55.0 [range=1–743] days; previous temozolomide=22 [73.3%] patients); all stopped therapy (radiologic progressive disease [PD], n=20; clinically unacceptable toxicities, n=7; follow-up loss, n=2; clinical PD, n=1). Mean relative dose intensity was 67.2% for napabucasin and 90.9% for temozolomide; 14/30 (46.7%) and 25/30 (83.3%) patients received ≥ 90% intended napabucasin and temozolomide doses, respectively. All patients reported ≥ 1 treatment-emergent adverse event (TEAE, grade ≤4); grade 3 TEAEs (≥ 10% patients) were diarrhea (23.3%, 7/30) and abdominal pain (16.7%, 5/30). One patient reported a grade 4 TEAE (seizure, treatment unrelated). PFS-6 was 28.1% (80% CI=16.8%-40.5%). Median PFS was 1.9 months (95% CI=1.8–3.3), with PFS-12 and PFS-18 both 16.8% (80% CI=7.8%-28.8%). ORR was 10% (95% CI=2.1%-26.5%), with 3 partial responses, 6 stable disease, 14 PD, and 7 patients not evaluated. OS-12 was 28.3%. The napabucasin-plus-temozolomide safety profile was consistent with that anticipated for each agent. Napabucasin (480 mg twice-daily) was associated with grade 3 diarrhea and suboptimal compliance. Antitumor effects were observed per the primary endpoint in this patient population.

Emibetuzumab plus ramucirumab: Simultaneous targeting of MET and VEGFR-2 in patients with advanced hepatocellular cancer in a phase 1b/2 study.

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 300-300 ◽  
Author(s):  
James J. Harding ◽  
Johanna C. Bendell ◽  
Charles S. Fuchs ◽  
Xuejing Wang ◽  
Volker Wacheck ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Hepatocellular Cancer ◽  
Primary Objective ◽  
Flat Dose ◽  
Phase 1B ◽  
Pre Treatment ◽  
Grade 3 ◽  
Expansion Cohort ◽  
Ecog Ps

300 Background: The mesenchymal-epithelial transition factor (MET) pathway is upregulated by anti-vascular endothelial growth factor (VEGF) therapies in vivo. Emibetuzumab (E) is a bivalent monoclonal anti-MET antibody that inhibits ligand-dependent and ligand-independent MET signaling. Here we report safety and initial anti-tumor activity for the combination of E plus ramucirumab (R), a human VEGFR-2 antibody in patients (pts) with advanced hepatocellular cancer (HCC) as part of a Phase 1b/2 study (NCT02082210). Methods: Pts with Child Pugh A advanced or metastatic HCC and no further standard therapy available received E (750 mg flat dose) and R (8mg/kg) intravenously every 2 weeks (Q2W) on a 28 day cycle. The primary objective was to evaluate safety and tolerability of the E+R dose and schedule in this patient population. As a co-primary objective, preliminary antitumor activity by RECIST v1.1 was studied. Exploratory objectives included evaluation of biomarkers for MET/HGF and VEGF pathways from fresh pre-treatment tumor biopsies. Results: As of July 2015, 15 pts were treated with E + R in the HCC expansion cohort. Most of the pts had ECOG PS of < 2, and prior sorafenib therapy. Ten pts (67%) experienced ≥ 1 drug-related adverse events (AEs). Commonly related AEs included fatigue (33%), peripheral edema (33%), hypertension (27%), and hypophosphatemia (27%). Most of these events were mild or moderate in severity and the only ≥ grade 3 related events reported included 1 case each of grade 3 fatigue, hypertension, neutropenia, leukopenia, and lymphopenia. In the 9 pts evaluable for response, there were 2 partial responses (PR; 1 unconfirmed, pt still ongoing) and 5 additional pts had stable disease for a disease control rate of 47% (7/15). Six pts were not evaluable and 5 pts remained on treatment at the time of data cut-off. Five pts received 4 or more cycles of therapy, including 1 pt ongoing in cycle 10. Both patients with PR were positive for MET expression. Updated results will be presented at the meeting. Conclusions: The combination of 750 mg E plus 8mg/kg R at Q2W demonstrated an acceptable safety profile and early evidence of antitumor activity in pts with advanced HCC. Clinical trial information: NCT02082210.

Safety and antitumor activity of ramucirumab plus pembrolizumab in treatment naïve advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma: Preliminary results from a multi-disease phase I study (JVDF).

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 101-101 ◽  
Author(s):  
Ian Chau ◽  
Nicolas Penel ◽  
Hendrik-Tobias Arkenau ◽  
Rafael Santana-Davila ◽  
Emiliano Calvo ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Median Duration ◽  
Gastroesophageal Junction ◽  
Objective Response ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Primary Objective ◽  
Antitumor Effects ◽  
Treatment Naïve ◽  
Ecog Ps

101 Background: Preclinical evidence suggests simultaneous blockade of vascular endothelial growth factor receptor 2 (VEGFR-2) and programed cell death 1 protein (PD-1) induces synergistic antitumor effects. We assessed safety and preliminary efficacy of ramucirumab (anti-VEGFR-2) plus pembrolizumab (anti-PD-1) in patients (pts) with treatment naïve advanced G/GEJ adenocarcinoma. Methods: This ongoing, multi-cohort, phase 1a/b trial enrolled ECOG PS 0-1 pts with treatment naïve advanced G/GEJ adenocarcinoma with measurable disease and baseline tumor tissue. PD-L1 status was assessed by DAKO PD-L1 22C3 IHC pharmDx assay using the combined positive score with ≥1% being positive. Ramucirumab was administered at 8 mg/kg on Days 1 & 8 with pembrolizumab 200 mg on Day 1 q3W. Primary objective was safety and tolerability of study treatment; preliminary efficacy was examined. Results: As of 31-July-2017, 28 treatment naïve G/GEJ adenocarcinoma pts were treated. Median age was 63 y, 75% male, 57% had ECOG PS of 0, and 68% were PD-L1 positive. At data cutoff, 8 (28%) pts continued to receive study treatment. Median duration of follow-up was 8.1 mo (IQR 6-10). Median treatment duration was 4.3 mo (IQR 2-7). All grades treatment-related adverse events (TRAEs) occurred in 27 (96%) of patients; TRAEs in ≥15% of pts were fatigue (36%), hypertension (25%) and headache (18%). Seventeen (61%) pts experience grade 3 TRAEs, most commonly hypertension (14%), diarrhea (11%), and elevated alanine (7%) or aspartate (7%) aminotransferase. No grade 4-5 TRAEs occurred. An objective response was achieved by 7 (25%) pts, 6 positive and 1 negative for PD-L1. Disease control rate was 68%. Median time to response was 2.7 mo (95% CI 1.3-2.8) and median duration of response was 10 mo (95% CI 9.7-10.3). Median progression-free survival was 5.3 mo (95% CI 3.2-11). Median overall survival has not been reached. Conclusions: Ramucirumab plus pembrolizumab demonstrated encouraging antitumor activity in treatment naïve advanced G/GEJ adenocarcinoma with no grade 4 TRAE observed. Clinical trial information: NCT02443324.

Tabelecleucel in combination with pembrolizumab (Pembro) in platinum-pretreated, recurrent/metastatic Epstein-Barr virus (EBV)-positive nasopharyngeal carcinoma (EBV+NPC).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS6092-TPS6092
Author(s):  
Lillian L. Siu ◽  
Joshua Bauml ◽  
Douglas Adkins ◽  
A. Dimitrios Colevas ◽  
Cesar Augusto Perez ◽  
...  
Keyword(s):  
Objective Response ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Phase 2 ◽  
Open Label ◽  
Barr Virus ◽  
Duration Of Response ◽  
Phase 1B ◽  
Epstein Barr ◽  
Favorable Safety

TPS6092 Background: Approximately 25% of patients (pts) with NPC develop RM disease, which has a poor prognosis (median overall survival [mOS]: 12–16 mo), despite standard treatments with radiation and/or chemotherapy. NPC is an EBV-associated cancer in which programmed cell death ligand 1 (PD-L1) expression is upregulated upon EBV activation. Pembro showed antitumor activity in a phase 1b study of pts with RM-NPC (objective response rate [ORR]: 26%; mOS: 16.5 mo) (Hsu, J Clin Oncol 2017;35:4050-56). Targeting RM EBV+ NPC with tab-cel immunotherapy (off-the-shelf, allogeneic EBV-specific T cells) in pts has also shown promise, with 2-yr OS rates of 84% (Prockop, ASCO 2016;34:3012). The favorable safety profile of tab-cel offers the opportunity for combination immunotherapy with pembro for increased efficacy. Methods: This multicenter, open-label, single-arm phase 1b/2 study evaluates safety and efficacy of tab-cel in combination with pembro. Study participants are ≥12 yrs of age with incurable, locally recurrent or metastatic EBV+ NPC previously treated with platinum-containing therapy. Pts are checkpoint-inhibitor naïve (phase 1b/2) or refractory to anti-PD-1 or anti-PD-L1 therapy (phase 1b). Tab-cel is selected from a bank based on matching ≥2 HLA alleles, including ≥1 restricting HLA allele, between pts and donors. Tab-cel will be administered intravenously (IV) on days 1, 8, and 15 of a 21-day cycle. Initial tab-cel dose is 2x106 cells/kg and the de-escalated tab-cel dose (if needed) is 1x106 cells/kg. Pembro is administered at 200 mg IV Q3W in adults and 2 mg/kg IV Q3W in pts aged 12 to 17 yrs. Primary outcomes of phase 1b are to characterize dose-limiting toxicities, identify the maximum tolerated dose (MTD) or in the absence of MTD, the recommended phase 2 dose, and assess safety. Primary outcomes for phase 2 are ORR and safety. Secondary endpoints include progression-free survival, OS, and duration of response. Enrollment is ongoing for 12-24 participants in the phase 1b portion of the study with a 6+6 design. Phase 2 is expected to enroll 36 pts. Clinical trial information: NCT03769467.

Phase 1b/2 study of binimetinib (BINI) in combination with nivolumab (NIVO) or NIVO plus ipilimumab (IPI) in patients (pts) with previously treated microsatellite-stable (MSS) metastatic colorectal cancer (mCRC) with RAS mutation.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. TPS870-TPS870 ◽  
Author(s):  
Johanna C. Bendell ◽  
Scott Kopetz ◽  
Mark R. Middleton ◽  
P. Taylor Eves ◽  
Viviana Bozon ◽  
...  
Keyword(s):  
Checkpoint Inhibitors ◽  
Mapk Pathway ◽  
Treatment Options ◽  
Primary Objective ◽  
Dose Finding ◽  
Phase 2 ◽  
Open Label ◽  
Ras Mutation ◽  
Previously Treated ◽  
Phase 1B

TPS870 Background: Approximately 96% of CRCs have an MSS phenotype, which results in more immunologically quiescent tumors for which immunotherapies are largely ineffective (Lee et al. 2015; Overman et al. 2016). Pts with MSS CRC and activating RAS mutation (35%–45% of CRCs) have treatment options limited still further because anti-EGFR monoclonal antibodies (eg, cetuximab) are ineffective owing to dominant activation of RAS in the MAPK pathway (Douillard et al. 2014). However, preclinical and preliminary clinical data suggest that MAPK pathway inhibition enhances antigen presentation and T-cell cytotoxicity to positively modulate the efficacy of checkpoint inhibitors (Brea et al. 2016; Bendell et al. 2014). The main objective of this open-label multicenter phase 1b/2 study is to evaluate whether the potential positive modulation of NIVO or NIVO plus IPI, when combined with BINI, translates into clinically meaningful overall response in pts with MSS mCRC and RAS mutation. Methods: The study will enroll ~90 previously treated pts (1 or 2 prior regimens), ~42 in phase 1b and ~48 in phase 2. The primary objective of phase 1b will be to determine the recommended phase 2 dose (RP2D) of BINI in combination with NIVO ± IPI. Dose finding in the doublet arm will begin with BINI 45 mg BID + NIVO 480 mg Q4W; the triplet arm will begin with the BINI RP2D from the doublet arm + NIVO 480 mg Q4W + IPI 1 mg/kg Q8W. In phase 2, pts will be randomized 1:1 to doublet or triplet arms, incorporating the BINI RP2Ds found in phase 1b; treatment will continue in 28-day cycles until disease progression, unacceptable toxicity, withdrawal of consent, initiation of subsequent anticancer therapy, loss to follow-up, or death. The primary objective for phase 2 will be to assess response by RECIST version 1.1. The study will also characterize safety and PK. CT.gov Identifier: Clinical trial information: NCT03271047.

scholarly journals Safety and efficacy of the combination of sonidegib and ruxolitinib in myelofibrosis: a phase 1b/2 dose-finding study

2020 ◽  
Vol 4 (13) ◽  
pp. 3063-3071
Author(s):  
Vikas Gupta ◽  
Denise Wolleschak ◽  
Hans Hasselbalch ◽  
Alessandro Maria Vannucchi ◽  
Steffen Koschmieder ◽  
...  
Keyword(s):  
Creatine Phosphokinase ◽  
Symptom Assessment ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Dose Finding ◽  
Phase 2 ◽  
Spleen Volume ◽  
Open Label ◽  
Phase 1B ◽  
Level 2

Abstract The sonidegib and ruxolitinib combination was assessed in an open-label study in JAK inhibitor-naive patients with myelofibrosis (MF). The primary objective of phase 1b was to establish the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) and phase 2 was to assess spleen volume reduction at weeks 24 and 48. Fifty patients were enrolled. In the dose-escalation phase (n = 23), doses for sonidegib once daily/ruxolitinib twice daily were 400/10 mg (level 1, n = 8), 400/15 mg (level 2, n = 10), and 400/20 mg (level 3, n = 5). Two patients had dose-limiting toxicity at level 2: increased blood creatine phosphokinase (grades 3 and 4, n = 1 each). MTD/RP2D was determined as sonidegib 400 mg daily + ruxolitinib 20 mg twice daily. In phase 1b expansion and phase 2 stage 1 (n = 27), by weeks 24 and 48, ≥35% reduction in spleen volume was observed in 44.4% and 29.6% patients, respectively. By weeks 24 and 48, 42.0% and 26.0% patients had ≥50% reduction in Myelofibrosis Symptom Assessment Form total symptom score, respectively. Most common treatment-related adverse events (grade 3/4) were increased blood creatine phosphokinase (18%), anemia (14%), and thrombocytopenia (12%). Four deaths were reported due to multiple organ dysfunction syndrome (on-treatment; no relationship with study treatment), acute myeloid leukemia, MF progression, and aspiration pneumonia. Although well tolerated, this combination will not be further developed in MF patients due to modest overall benefit compared with historical ruxolitinib monotherapy. This trial was registered at www.clinicaltrials.gov as #NCT01787552.

scholarly journals A phase 1b study of AFM13 in combination with pembrolizumab in patients with relapsed or refractory Hodgkin lymphoma

Blood ◽  
2020 ◽  
Vol 136 (21) ◽  
pp. 2401-2409 ◽  
Author(s):  
Nancy L. Bartlett ◽  
Alex F. Herrera ◽  
Eva Domingo-Domenech ◽  
Amitkumar Mehta ◽  
Andres Forero-Torres ◽  
...  
Keyword(s):  
Hodgkin Lymphoma ◽  
Immune Cell ◽  
Response Rate ◽  
Objective Response ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Population Pharmacokinetic ◽  
Dose Escalation Study ◽  
Phase 1B ◽  
Refractory Hodgkin Lymphoma

Abstract In relapsed/refractory Hodgkin lymphoma (R/R HL), immunotherapies such as the anti-programmed death-1 inhibitor pembrolizumab have demonstrated efficacy as monotherapy and are playing an increasingly prominent role in treatment. The CD30/CD16A-bispecific antibody AFM13 is an innate immune cell engager, a first-in-class, tetravalent antibody, designed to create a bridge between CD30 on HL cells and the CD16A receptor on natural killer cells and macrophages, to induce tumor cell killing. Early studies of AFM13 have demonstrated signs of efficacy as monotherapy for patients with R/R HL and the combination of AFM13 with pembrolizumab represents a rational new treatment modality. Here, we describe a phase 1b, dose-escalation study to assess the safety and preliminary efficacy of AFM13 in combination with pembrolizumab in patients with R/R HL. The primary objective was estimating the maximum tolerated dose; the secondary objectives were to assess safety, tolerability, antitumor efficacy, pharmacokinetics, and pharmacodynamics. In this heavily pretreated patient population, treatment with the combination of AFM13 and pembrolizumab was generally well tolerated, with similar safety profiles compared to the known profiles of each agent alone. The combination of AFM13 with pembrolizumab demonstrated an objective response rate of 88% at the highest treatment dose, with an 83% overall response rate for the overall population. Pharmacokinetic assessment of AFM13 in the combination setting revealed a half-life of up to 20.6 hours. This proof-of-concept study holds promise as a novel immunotherapy combination worthy of further investigation. This phase 1b study was registered at www.clinicaltrials.gov as NCT02665650.

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