P3.02c-046 Safety, Clinical Activity and Biomarker Results from a Phase Ib Study of Erlotinib plus Atezolizumab in Advanced NSCLC

2581 Background: Progression-free survival (PFS) and response to EGFR tyrosine kinase inhibitors (TKIs) vary in p with NSCLC driven by EGFR mutations. In our experience, high BRCA1 mRNA expression was associated with shorter PFS in EGFR-mutant p treated with erlotinib. We hypothesized that since olaparib downregulates BRCA1 expression, the addition of olaparib to gefitinib could improve PFS in these p. Methods: This is a Phase IB dose escalation study to identify the maximum tolerated dose (MTD), dose limiting toxicity (DLT), pharmacokinetics, and clinical activity of orally administered olaparib in combination with gefitinib in EGFR-mutant advanced NSCLC p. In a standard 3+3 design, p were treated with gefitinib 250mg once daily plus olaparib tablets at escalating doses ranging from 100mg BID to 250mg TDS during a 28-day cycle. Results: 18 p have been included across four dose levels of olaparib: 100mg BID (3), 200mg BID (6), 200mg TDS (3) and 250mg TDS (6). Median age, 69; male, 4; PS 0, 17; EGFR TKI treatment-naïve, 10. Toxicities: anemia (66.6%), leucopenia (33.3%), nausea (33.3%), diarrhea (33.3%), asthenia (27.7%), rash (22.2%) vomiting (11%), decreased appetite (16%), and hyperlipasemia (5.5%). Most toxicities were G1-2; G3 drug-related events included leucopenia (1) and anemia (3). No DLT at dose levels 1, 2, and 3; 1 DLT at dose level 4 (G3 anemia and repeated blood transfusion within 4-6 weeks). Few dose reductions or interruptions were needed. 1 p died due to pulmonary embolism unrelated to treatment. Partial responses (PR) were observed in 7 p (41.1%), all EGFR TKI-naïve; stable disease (SD) in 7 (41.1%), most previously treated; progressive disease (PD) in 3 (17.6%), all previously treated. Durable PR and SD were observed in EGFR TKI-naïve and previously treated p. 8 patients are still on treatment. Enrollment to dose level 4 will be completed in February 2013. Conclusions: This phase IB trial of gefitinib plus olaparib, has confirmed the activity and tolerability of the combination. The final recommended dose of olaparib is expected to be between 200 and 250 mg TDS. A phase II randomized trial in treatment-naïve EGFR-mutant advanced NSCLC will be opened in 2013. Clinical trial information: NCT0151317.

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441O Preliminary safety and clinical activity of erlotinib plus atezolizumab from a Phase Ib study in advanced NSCLC

Annals of Oncology ◽

10.1093/annonc/mdw594.005 ◽

2016 ◽

Vol 27 (suppl_9) ◽

Cited By ~ 18

Author(s):

B.B.Y. Ma ◽

C.M. Rudin ◽

A. Cervantes ◽

A. Dowlati ◽

D. Costa ◽

...

Keyword(s):

Advanced Nsclc ◽

Clinical Activity ◽

Phase Ib

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Safety and clinical activity results from a phase Ib study of alectinib plus atezolizumab in ALK+ advanced NSCLC (aNSCLC).

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.15_suppl.9009 ◽

2018 ◽

Vol 36 (15_suppl) ◽

pp. 9009-9009 ◽

Cited By ~ 21

Author(s):

Dong-Wan Kim ◽

Shirish M. Gadgeel ◽

Scott N. Gettinger ◽

Gregory J. Riely ◽

Geoffrey R. Oxnard ◽

...

Keyword(s):

Advanced Nsclc ◽

Clinical Activity ◽

Phase Ib

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441O Preliminary safety and clinical activity of erlotinib plus atezolizumab from a Phase Ib study in advanced NSCLC

Annals of Oncology ◽

10.1016/s0923-7534(21)00599-8 ◽

2016 ◽

Vol 27 ◽

pp. ix141

Author(s):

B.B.Y. Ma ◽

C.M. Rudin ◽

A. Cervantes ◽

A. Dowlati ◽

D. Costa ◽

...

Keyword(s):

Advanced Nsclc ◽

Clinical Activity ◽

Phase Ib

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A phase Ib study of NUC-3373 in combination with standard therapies in advanced/metastatic colorectal cancer (NuTide:302).

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.3_suppl.93 ◽

2021 ◽

Vol 39 (3_suppl) ◽

pp. 93-93

Author(s):

Andrew L. Coveler ◽

Farasat Kazmi ◽

Kristen Keon Ciombor ◽

Janet Graham ◽

Lisa Jane Rodgers ◽

...

Keyword(s):

Safety Profile ◽

Safety Data ◽

Resistance Mechanisms ◽

Clinical Activity ◽

Data Series ◽

Rapid Progression ◽

Phase Ib ◽

Toxic Metabolites ◽

Anti Cancer ◽

Cancer Agent

93 Background: 5-FU is a key anti-cancer agent used across a broad range of tumors. The anti-cancer metabolite of 5-FU, fluorodeoxyuridine-monophosphate (FUDR-MP), binds and inhibits thymidylate synthase (TS), disrupting DNA synthesis and repair. 5-FU is often dosed with leucovorin (LV) to enhance the binding of FUDR-MP to TS. NUC-3373 is a targeted inhibitor of TS designed to bypass 5-FU resistance mechanisms associated with transport, activation and breakdown and avoid the generation of toxic metabolites such as FUTP and FBAL. NUC-3373 has a longer plasma t1/2 (~10 hours) than 5-FU (8-14 minutes), generating substantially higher intracellular levels of FUDR-MP and lower levels of the toxic metabolites FUTP and FBAL. Part 1 interim data from the NuTide:302 study demonstrated NUC-3373’s favorable PK and safety profile was unaffected by LV. Therefore, all subsequent patients in NuTide:302 are receiving NUC-3373 + LV. Here we present the next data series from NuTide:302. Methods: NuTide:302 is a 3-part, Phase Ib study in patients with advanced CRC who have relapsed after ≥2 prior lines of fluoropyrimidine- containing therapies. In Part 1, patients are receiving NUC-3373 with or without LV. In Part 2, NUC-3373 +LV is being administered in dose-escalation cohorts with either oxaliplatin (NUFOX) or irinotecan (NUFIRI). In Part 3, the NUFOX and NUFIRI regimens selected from Part 2 will be combined with biologics targeting VEGF and EGFR pathways. Results:36 patients have been treated in Part 1: 21 received 1500 mg/m2 NUC-3373 ± LV q2w; 11 received 1500 mg/m2NUC-3373 + LV q1w; and 4 received 2500 mg/m2 NUC-3373 + LV q1w. Clinical activity has been observed including tumor shrinkages and stabilization of disease for up to 5 months following rapid progression (≤2 months) on prior lines of therapy. One fluoropyrimidine-refractory patient demonstrated a 28% reduction in target lesions and achieved a stable disease of 5 months after rapid progression on CAPOX (2 months) and FOLFIRI (1.5 months). Safety data for all patients treated with NUC-3373 ± LV in Part 1 of NuTide:302 is shown below. Updated data on the clinical activity and safety of NUC-3373 will be presented. Clinical trial information: NCT03428958. Conclusions:NUC-3373 ± LV has shown clinical activity in heavily pre-treated CRC patients, including tumor shrinkage in a fluoropyrimidine-refractory patient. The safety profile of NUC-3373 ± LV is very encouraging: no neutropenia or hand-foot syndrome of any grade and no diarrhea or mucositis above Grade 2. NUC-3373 +LV is currently being dose escalated further in Part 1 and dosed with either oxaliplatin (NUFOX) or irinotecan (NUFIRI) in Part 2 of NuTide:302. [Table: see text]

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A phase Ib/II study of selinexor in combination with imatinib in patients with advanced gastrointestinal stromal tumor (GIST): SeliGIST/GEIS-41 trial.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.11534 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 11534-11534

Author(s):

Cesar Serrano ◽

Claudia Valverde ◽

Josefina Cruz Jurado ◽

Javier Martinez-Trufero ◽

Xavier Guri ◽

...

Keyword(s):

Clinical Benefit ◽

Nuclear Export ◽

Single Agent ◽

Progression Free Survival ◽

Antitumoral Activity ◽

Clinical Activity ◽

Activity Data ◽

Phase Ib ◽

Best Response ◽

Heavily Pretreated

11534 Background: KIT or PDGFRA oncogenic activation drives GIST progression throughout the disease course. Accordingly, currently approved agents in metastatic GIST focus on the therapeutic suppression of these receptors. However, the clinical benefit after imatinib (IM) progression is still modest, suggesting the co-operation of KIT/PDGFRA-independent mechanisms in GIST cell survival. Selinexor is an oral, selective inhibitor of XPO1-mediated nuclear export, and preclinical studies evidenced antitumoral activity in GIST as single agent and in combination with IM in both IM-sensitive and IM-resistant models. Methods: The phase Ib portion studied IM 400 mg daily plus weekly selinexor in patients (pts) with IM-resistant, advanced GIST. Prior intolerance to IM was not allowed. A standard 3+3 dosing schema was utilized to determine the recommended phase II dose (RP2D) of this combination. Investigator-assessed response was evaluated every 8 weeks using RECIST 1.1. Results: At data cutoff of Sep 25, 2020, 12 pts were enrolled and received treatment with IM 400 mg and selinexor once weekly at dose levels (DL) 1 (60 mg), DL2 (80 mg) and DL3 (100 mg). Median age 57 (range 46-77), 42% female, median prior therapies 4 (range 2-7). Although only 1/6 pts developed a dose limiting toxicity (DLT) at DL3, the RP2D was defined at DL2 (IM 400 mg daily and selinexor 80 mg once weekly) based on activity data in the DL2 and the need for dose reductions in 5/6 pts at DL3 after the DLT window. All pts were evaluable for toxicity and response. One DLT occurred at DL3 (G3 nausea). Non-DLT G3/4 toxicities were anemia (1/12 pts), neutropenia (1/12 pts), vomiting (1/12 pts) and fatigue (2/12 pts). Common G1/2 toxicities were nausea (11/12 pts), vomiting (10/12 pts), neutropenia (5/12 pts) and anemia, fatigue, diarrhea, and periorbital edema (4/12 pts each). No unexpected toxicities were observed. Overall response rate in the 12 pts evaluable for response was 67% (95% CI 0.349-0.901), with 2 pts achieving PR (17%) and 6 pts SD (50%) as the best response. Clinical benefit rate (CBR = CR, PR, SD) ≥ 16 weeks was 42% (95% CI 0.157-0.723). Median progression free survival was 3.5 months (95% CI 1.7-7.3). Four pts remain on trial at data cutoff. Conclusions: IM and selinexor combination is well-tolerated and has clinical activity in heavily pretreated GIST pts. The trial is currently exploring selinexor as single agent in the IM-resistant GIST population. Clinical trial information: NCT04138381.

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