A phase I study of R04929097, an oral gamma secretase inhibitor, in combination with gemcitabine in patients with advanced solid tumors (PHL-078/CTEP 8575).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3082-3082 ◽  
Author(s):  
Sue Richter ◽  
Elaine McWhirter ◽  
Eric Xueyu Chen ◽  
Ben Tran ◽  
Sebastien J. Hotte ◽  
...  
Keyword(s):  
Notch Signaling ◽  
Solid Tumors ◽  
Maculopapular Rash ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Advanced Solid Tumors ◽  
Gamma Secretase ◽  
Best Response ◽  
Recommended Phase Ii Dose ◽  
To Receive

3082 Background: RO4929097 (RO) is an oral inhibitor of γ-secretase that disrupts Notch signaling. Gemcitabine (GEM) is active against many solid tumors with a favorable toxicity profile suited to combination. The primary objective of this trial is to establish the recommended phase II dose (RP2D) of RO in combination with GEM; secondary objectives include the evaluation of safety, tolerability, pharmacokinetics (PK), biomarkers of Notch signaling and preliminary anti-tumor activity. Methods: Patients (pts) with advanced solid tumors were enrolled in escalating RO dose levels (DL) as follows: DL1 20mg, DL2 30mg; DL3 45mg and DL4 90mg using a 3+3 design. Treatment with RO was administered once daily on days (d) 1-3, 8-10, 15-17, 22-24 and GEM 1000mg/m2 on d1, 8, and 15 in 28d cycles (c). Dose limiting toxicities (DLTs) during c1 were defined as CTCAE v4 grade (g) 3 non-hematological or g4 hematological toxicities, failure to start c2 within <14 days, or failure to receive ≥75% doses of RO or d8 GEM in c1. Serial plasma samples for RO PK were collected on d1 and 10. Results: As of January 2012, 15 pts (median age 55) have been treated. DLTs were: DL1 0/3, DL2 1/7 (g3 ALT), DL3 0/3, DL4 2/2 (g3 AST/ALT and failure to receive ³75% doses); all were reversible. One death (perforated viscus) related to disease progression was observed. Most common g1/2 toxicities were nausea (9), vomiting (6), fatigue (5), hypophosphatemia (5), transaminitis (3) hypomagnasemia (2) and maculopapular rash (2). G3 hypophosphatemia (1) was observed beyond C1. RO PKs demonstrated comparable exposures at 30mg and 45mg (Table). Best response (RECIST 1.1) was stable disease > 4 months in 3 pts (pancreas, tracheal, breast CA). Conclusions: RO and GEM can be safely combined. RO levels achieved exceeded the AUC0-24 for efficacy in preclinical models using daily dosing. The maximum tolerated dose was exceeded at 90mg RO. Dose expansion at 45mg RO is ongoing to confirm the RP2D. [Table: see text]

Phase I study of oral S-1 in combination with oxaliplatin (oxali) and bevacizumab (bev) in patients with advanced solid tumors

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 4091-4091
Author(s):  
J. Zhang ◽  
K. Chung ◽  
C. Zergebel ◽  
P. Urrea ◽  
M. Quinones ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Solid Tumors ◽  
Dose Level ◽  
Cyanuric Acid ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Advanced Solid Tumors ◽  
Clinical Pharmacokinetics ◽  
Progression Of Disease ◽  
Recommended Phase Ii Dose

4091 Background: S-1 is a novel oral fluoropyrimidine (tegafur, CDHP and potassium oxonate) designed for enhanced DPD inhibition and reduced GI toxicity. Bev and oxali have demonstrated safety and synergistic anti-tumor activity with oral and IV fluoropyrimidines. The primary objective is to investigate the safety and maximum tolerated dose (MTD) of S-1 combined with bevacizumab and oxaliplatin in patients with advanced solid tumors. Secondary objective is to investigate the clinical pharmacokinetics (PK) of the components of S-1 (FT, CDHP, Oxo), 5-FU, a-fluoro-β-alanine, cyanuric acid, uracil, and oxali and to document any antitumor activity. Methods: ECOG 0/1 patients with advanced or metastatic solid tumors received oral S-1 starting at 20 mg/m2/dose BID x 14 days (classic 3+3 cohort dose escalation by 5mg/m2/dose until MTD), plus fixed doses of bev 7.5 mg/kg IV day 1, and Oxali 130 mg/m2 IV day 1 of every 3 week cycle, with discontinuation of oxali after 4 cycles. Reintroduction of oxali was allowed upon progression of disease. Toxicity, antitumor activity and PKs were assessed. The MTD was defined as the highest dose level at which < 33% of the patients experience a dose- limiting toxicity (DLT) during the first 2 cycles. Results: Of 22 evaluable patients, 3 patients were treated at 20mg/m2 S1 and 13 patients were treated at 25mg/m2 S1 without a DLT. At 30mg/m2, two patients experienced a DLT(Grade 3 diarrhea, Grade 4 mucositis). The MTD and recommended phase II dose of S-1 is 25mg/m2 in combination with oxali and bev. A median of 8 cycles of S-1 were initiated at the 25 mg/m2 dose level. Common MTD level toxicities included fatigue (62%), nausea (62%) and diarrhea (46%), with no grade 4 toxicities observed. Best responses (RECIST): stable disease(16 patients), partial response (2 patients), non-measurable disease (3 patients). The Day 8 AUC(0–8) of 5-FU at 20/25/30 mg/m2 dose level were 230±115 hr*ng/ml, 470±172 hr*ng/ml and 502±169 hr*ng/ml, respectively. Conclusions: The MTD combination of 25mg/m2 S-1, oxali and bev can be given safely. The study will be expanded to test S-1 one week on, one week off schedule in combination with oxali/bev every two weeks. No significant financial relationships to disclose.

scholarly journals Preclinical investigations and a first-in-human phase I trial of M4112, the first dual inhibitor of indoleamine 2,3-dioxygenase 1 and tryptophan 2,3-dioxygenase 2, in patients with advanced solid tumors

2020 ◽  
Vol 8 (2) ◽  
pp. e000870
Author(s):  
Aung Naing ◽  
Joseph P Eder ◽  
Sarina A Piha-Paul ◽  
Claude Gimmi ◽  
Elizabeth Hussey ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Phase I Trial ◽  
Ex Vivo ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Advanced Solid Tumors ◽  
Antitumor Effects ◽  
Dual Inhibitor ◽  
Indoleamine 2,3 Dioxygenase

BackgroundM4112 is an oral, potent, and selective indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase 2 (TDO2) dual inhibitor. Here, we report preclinical data and first-in-human phase I data, including safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy, of M4112 monotherapy in patients with advanced solid tumors.MethodsIn preclinical studies, M4112 was administered to mice with IDO1-expressing tumors to determine tumor IDO1 and liver TDO2 inhibition. In the phase I trial, patients received doses of M4112 two times per day in 28-day cycles until progression, toxicity, or withdrawal of consent. The primary objective was to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D). The primary endpoint was the incidence of dose-limiting toxicities (DLTs), treatment-emergent adverse events (TEAEs), and treatment-emergent changes in safety parameters. Other endpoints included pharmacokinetics, pharmacodynamics, and antitumor effects.ResultsIn mice, M4112 significantly decreased the kynurenine:tryptophan ratio in the liver and tumor. Fifteen patients received M4112 at five distinct dose levels (three patients per cohort: 100, 200, 400, 600, and 800 mg two times per day orally). Initially, all doses inhibited IDO1 ex vivo, but plasma kynurenine levels returned to or exceeded baseline levels after day 15. Despite initial changes in kynurenine, there was no significant reduction of plasma kynurenine at steady state. There was one DLT (grade 3 allergic dermatitis; 800 mg two times per day) and one grade 2 QT prolongation (800 mg two times per day), resulting in dose reduction (not a DLT). M4112 was well tolerated, and neither the MTD nor the RP2D was established. TEAEs included fatigue, nausea, and vomiting. The best overall response was stable disease (n=9, 60%).ConclusionsThere were no serious safety concerns at any dose. Although M4112 inhibited IDO1 activity ex vivo, plasma kynurenine levels were not reduced despite achieving target exposure.Trial registration numberNCT03306420.

Pemetrexed in combination with paclitaxel: A phase I clinical and pharmacokinetic trial in patients with solid tumors

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2051-2051 ◽  
Author(s):  
T. Graefe ◽  
C. Bolling ◽  
C. Lubbing ◽  
J. Latz ◽  
J. Blatter ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Thyroid Carcinoma ◽  
Phase Ii ◽  
Single Agent ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Recommended Dose ◽  
Clinical Activity ◽  
Best Response ◽  
Recommended Phase Ii Dose

2051 Background: Pemetrexed (Alimta [AL]) and paclitaxel (P) are clinically active in a variety of tumors. The primary objective of this trial was to determine the maximum tolerated dose (MTD) of the ALP combination; secondary objectives were: determination of dose-limiting toxicities (DLTs), definition of a recommended phase II dose, pharmacokinetic (PK) characterization and the anecdotal collection of antitumor activity. Methods: Escalating doses of P (3h infusion, d1 and d8) and AL (10 min infusion, d8 prior to P) were given in a 21d cycle. Results: 59 patients (pts) were enrolled. DLTs occurred at the following ALP (mg/m2) doses: 400/30 [G3 bilirubin (b), G3 and G4 thrombocytopenia (plts)]; 500/30 (G4 plts); 500/40 (G3 b); 500/75 (G4 ANC); 500/100 (G4 leukopenia, G4 ANC). With G4 leukopenia and G4 ANC in 4/6 pts and febrile neutropenia in 1 pt, the MTD was reached at the ALP (mg/m2) dose of 500/120. To confirm safety at the recommended dose-level, another 6 patients were treated at the ALP (mg/m2) dose of 500/100. 18 pts [mesothelioma (3), esophagus (2), lung (1), liver (1), renal (1), stomach (1), thyroid (9)] showed stable disease as best response. 4/14 (29%) pts with thyroid carcinoma showed long lasting partial responses [duration (months) 29+, 22, 18, 15]. One additional PR (2) was observed in a pt with penile carcinoma. AL PK when administered with P were consistent with those for AL administered as a single-agent. Conclusions: The ALP combination is safe and shows broad clinical activity. 500/100 mg/m2 is the recommended dose for further studies. Promising antitumor activity was observed in thyroid cancer. A phase II trial in thyroid carcinoma will be conducted. [Table: see text]

A phase I study of ISIS 481464 (AZD9150), a first-in-human, first-in-class, antisense oligonucleotide inhibitor of STAT3, in patients with advanced cancers.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 8523-8523 ◽  
Author(s):  
David S. Hong ◽  
Anas Younes ◽  
Luis Fayad ◽  
Nathan Hale Fowler ◽  
Fredrick B. Hagemeister ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Antisense Oligonucleotide ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Dose Escalation Study ◽  
Mantle Cell ◽  
Prior Systemic Therapy ◽  
Recommended Phase Ii Dose ◽  
Transcription 3 ◽  
Clinical Trial Information

8523 Background: ISIS 481464 is a synthetic bicyclic nucleic acid-containing antisense oligonucleotide that is complementary to the mRNA for signal transducer and activator of transcription 3 (STAT3). Methods: Primary objective of the dose-escalation study (3+3 design) was to establish the maximum tolerated dose (MTD) and recommended phase II dose (RP2D). Secondary objectives included safety, tumor response, pharmacokinetics (PK), and pharmacodynamics (PD) using IL-6 and tumor markers. Patient (pt) eligibility included : >18 yrs old, solid tumors or lymphomas refractory to at least 1 prior systemic therapy. ISIS 481464 was administered IV as a loading dose on Days 1, 3, and 5 and then weekly. Results: 15 pts were dosed (4 at 2 mg/kg and 11 at 4 mg/kg). 6 pts had advanced lymphoma (3 DLBCL, 2 Hodgkin’s lymphoma, 1 mantle cell lymphoma) and 9 pts solid tumors. There was one dose limiting toxicity (DLT), a possibly related thrombotic microangiopathy at 4 mg/kg. Treatment emergent thrombocytopenia was observed with an average reduction of approximately 70% from baseline. Three pts, 1 at 2 mg/kg and 2 at 4 mg/kg, experienced nadirs in platelet count below 50x109/L (range 16 to 33x109/L). MTD was not reached; however, given the thrombocytopenia at 4mg/kg, the RP2D was 2mg/kg. Partial responses were observed in 2/3 DLBCL pts. The 1st DLBCL pt (2 mg/kg) with 10 prior treatments had a durable 55% reduction in tumor size and is ongoing treatment at 11 months. This pt had a 76% reduction in IL-6. The 2nd DLBCL pt (4 mg/kg) with 2 prior treatments had a 65% reduction for 4 months and was able to undergo autologous stem cell transplantation. There were no responses in the solid tumor pts. PKs revealed increased plasma trough levels (indicative of tissue concentrations) with increased dose. Conclusions: ISIS 481462 was well-tolerated and the RP2D was determined to be 2 mg/kg. Initial tumor activity was observed in DLBCL pts and a dose expansion in advanced lymphomas is ongoing. Clinical trial information: NCT01563302.

First-in-human dose escalation study of LY2875358 (LY), a bivalent MET antibody, as monotherapy and in combination with erlotinib (E) in patients with advanced cancer.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 8093-8093 ◽  
Author(s):  
Jonathan Wade Goldman ◽  
Lee S. Rosen ◽  
Alain Patrick Algazi ◽  
Patricia Kellie Turner ◽  
Volker Wacheck ◽  
...  
Keyword(s):  
Adverse Events ◽  
Solid Tumors ◽  
Advanced Nsclc ◽  
Single Agent ◽  
Primary Objective ◽  
Advanced Solid Tumors ◽  
Serious Adverse Events ◽  
Dose Escalation Study ◽  
Human Dose ◽  
Recommended Phase Ii Dose

8093 Background: Activation of the hepatocyte growth factor (HGF)/MET receptor pathway promotes tumor growth, invasion and dissemination. LY is a humanized IgG4 monoclonal bivalent antibody against MET which inhibits ligand dependent- and ligand independent activation of MET. Based on preclinical results, we examined LY alone in patients with advanced solid tumors and LY+E in advanced NSCLC patients. Methods: LY monotherapy was administered 20-2,000 mg Q2W IV to 23 patients with advanced solid tumors. Combination therapy with 700-2,000 mg Q2W IV of LY and E (150 mg QD) was completed in 14 patients with advanced NSCLC. The primary objective was to determine a recommended phase II dose (RPTD) for LY and LY+E. Secondary objectives included assessment of toxicity, PK, PD (including MET extracelluar domain and HGF), and antitumor activity. Results: LY and LY+E were well tolerated. No dose-limiting toxicities, serious adverse events, or ≥ Grade 3 adverse events (AEs) possibly related to LY have been observed. The most frequent (≥5% of patients) AEs possibly related to LY2875358 monotherapy were nausea (8.7 %), vomiting (8.7%), and diarrhea (8.7%). The most frequent (≥10% of patient) grade 1 or 2 adverse event possibly related to LY2875358 in patients treated with LY+E were fatigue (21.4%) and anorexia (14.3%). Durable PR according to RECIST were observed for LY (n=1) and LY+E (n=2 out of 13 evaluable patients; both PR patients positive for MET protein expression). Conclusions: LY appears to be safe when administered as single agent and in combination with E up to 2,000 mg Q2W IV. The RPTD of LY is 750 mg Q2W IV for monotherapy and in combination with E based on PK/PD data. Clinical trial information: NTC 01287546.

Phase I pharmacokinetic (PK), and pharmacodynamic (PD) trial of the novel oral Notch inhibitor MK-0752 in patients (pts) with advanced breast cancer (BC) and other solid tumors

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 10574-10574 ◽  
Author(s):  
I. E. Krop ◽  
M. Kosh ◽  
I. Fearen ◽  
J. Savoie ◽  
A. Dallob ◽  
...  
Keyword(s):  
Notch Signaling ◽  
Solid Tumors ◽  
Dose Level ◽  
Target Genes ◽  
Maximum Tolerated Dose ◽  
Gamma Secretase ◽  
Post Dose ◽  
Grade 3 ◽  
600Mg Daily

10574 Introduction: Activation of Notch signaling occurs in ∼40% of human BCs and high Notch expression is associated with poor outcome. Inhibition of Notch inhibits BC cell proliferation in vitro. Notch signaling requires gamma secretase (GS), which cleaves Notch, releasing the Notch intracellular domain (NICD) to activate transcription of target genes. MK-0752 is a potent GS inhibitor. Methods: In Part 1 of the study, pts with advanced solid tumors were enrolled using an accelerated dose escalation with 1 pt/dose level until the occurrence of ≥Grade 2 toxicity, then 3–6 pts/dose level. MK-0752 was administered by once-daily oral dosing in 28-day cycles. Once a maximum tolerated dose (MTD) was established, an additional 22 pts with advanced BC were to be enrolled in Part 2. Six-point PK plasma profiles were collected over 24 hours on Days 1 and 28 and assayed by LC/MS/MS. PD measurement of plasma Abeta40 peptide (another gamma secretase substrate) was performed pre/post dose on Days 1 and 28. Tumor biopsies on Days 1 and 28 were obtained from a subset of pts to assess changes in Notch activity by immunohistochemical analysis of NICD. Results: In Part 1, two pts were enrolled at 450mg daily, and five pts at 600mg daily. Dose-limiting toxicities (DLTs) were Grade 3 diarrhea, constipation, nausea, and abdominal cramping at 600 mg. In Part 2, an additional 14 pts with BC were enrolled at 450mg daily. In this cohort, Grade 2/3 fatigue requiring dose reduction occurred in 6 pts. Grade 3 diarrhea (1pt), nausea (1 pt) and elevated liver transaminases (2 pt) were also observed. Mean PK parameters (at 450mg, 600 mg) on Day 1 were AUC0–24hr = 1036, 1065μM·hr, Cmax = 72, 61μM, C24hr = 25, 32μM, and tmax = 3, 7 hr. PD measurements of GS inhibition showed a 12–78% (mean 46%) decrease in plasma Abeta40 at 4 hours on Day 1 compared to predose. Conclusion: Continuous dosing of MK-0752 at 450mg daily in pts with BC was associated with significant toxicity, predominantly fatigue, and cannot be considered a MTD. An intermittent dosing schedule is being explored. MK-0752 at all doses inhibited GS, as demonstrated by decreases in plasma Abeta40. Analysis of efficacy and intratumoral Notch inhibition will be reported at the meeting. [Table: see text]

Phase I and pharmacokinetics (PK) study of sequential paclitaxel and trabectedin every 2 weeks in patients with advanced solid tumors

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2029-2029 ◽  
Author(s):  
K. P. Papadopoulos ◽  
Q. Chu ◽  
A. Patnaik ◽  
M. M. Mita ◽  
J. Cooper ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Phase I ◽  
Solid Tumors ◽  
Geometric Mean ◽  
Single Agent ◽  
Median Number ◽  
Maximum Tolerated Dose ◽  
Advanced Solid Tumors ◽  
M Cell ◽  
Recommended Phase Ii Dose

2029 Background: Trabectedin (ET-743) is a DNA minor-groove intercalating agent that blocks transcription factor activity, elicits G2/M cell cycle arrest, and induces apoptosis. Single agent activity has been demonstrated in soft tissue sarcoma (STS), breast, prostate and ovarian cancer. In preclinical studies sequential exposure of paclitaxel (P) followed by trabectedin (T) 24 hrs later resulted in synergy. The objectives of this phase I study were to determine the maximum tolerated dose (MTD) and recommended phase II dose (RD) of sequential P and T administered every 2 weeks in patients with advanced solid tumors. Methods: Escalating doses of P (80–120 mg/m2) over 1hr iv on day 1 and T ( 525–775 μg/m2) as 3 hrs iv day 2 every 2 weeks were administered. To evaluate drug:drug interactions, P was administered alone on day -7 in course 1 and PK studies performed courses 1 & 2. MTD was defined as ≥ 2/3 pts with dose limiting toxicity (DLT) in the 1st 2 courses. Results: 29 pts were enrolled and 27 were evaluable: median age was 48 yrs (19–82). M/F 16/13. Pts were treated over 5 dose levels: I 80/525 (n = 3), II 80/580 (n = 3), III 120/580 (n = 6), IV 120/650 (n = 11), V 120/775 (n = 4). A total of 213 courses of therapy were given, median number of course was 4 (range 1–28). There were 4 DLTs due to neutropenia delaying therapy > 1 week; one each at 120/580 (Grade 2) and 120/650 (Grade 4) and 2 at the MTD of 120/775 (Grade 4). Most common toxicities observed for P+T were neutropenia (24%), nausea (51%), vomiting (24%), transaminitis (23%), myalgia (24%) and alopecia (20%). One pt with PNET has an ongoing CR 16 months, one breast cancer pt (prior P failure) has PR 12 mo+ and 8 pts (6 STS) had SD > 3 mo (range 4–15 mo). There appear to be no marked drug:drug interactions for P and T. Preliminary non-compartmental PK results [geometric mean (CV%)] for T include t1/2 52.4 hr (43.6%); Cl l/hr/m2 31.6 (57.3%); Vss l/m2 1382 (69%) and for P are t1/2, 29.2 hr (39.1%); Cl l/hr/m2 15.3 (44.1%); Vss 213 l/m2 (72%). Conclusions: The recommended dose for this combination is paclitaxel 120 mg/m2 day 1 and trabectedin 650 μg/m2 day 2 administered every 2 weeks. Antitumor activity in STS and breast cancer, predictable PK parameters, and tolerable toxicity warrants further study of this combination. [Table: see text]

Open-label, multicenter, phase I study to assess safety and tolerability of adavosertib plus durvalumab in patients with advanced solid tumors.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 2562-2562 ◽  
Author(s):  
Manish R. Patel ◽  
Gerald Steven Falchook ◽  
Judy Sing-Zan Wang ◽  
Esteban Rodrigo Imedio ◽  
Sanjeev Kumar ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Phase I Study ◽  
Human Monoclonal Antibody ◽  
Maximum Tolerated Dose ◽  
Preliminary Evidence ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Drug Induced ◽  
Recommended Phase Ii Dose

2562 Background: Adavosertib (AZD1775; A) is a highly selective inhibitor of WEE1. This Phase I study (NCT02617277) investigated a range of doses and schedules for oral A plus IV durvalumab (DV), a human monoclonal antibody targeting PD-L1, to determine the maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) in patients (pts) with advanced solid tumors. Methods: Four 28-day schedules (Sch) were evaluated with pts receiving DV 1500 mg on day (d) 1 of each schedule (Table). Patients continued treatment if they showed clinical benefit in the absence of any discontinuation criteria. Pts received A monotherapy for PK analysis prior to the start of combination therapy in Sch B, C (d –7 to –5) and D (d –9 to –5). MTD was determined using a 3+3 dose-escalation cohort design. Predefined dose-limiting toxicities (DLTs) were evaluated during the first cycle of study treatment. Results: 54 pts received A (most common primary tumor sites: colon, 19%; lung, 13%; breast, 11%). The most common grade ≥3 AEs were fatigue (15%), diarrhea (11%) and nausea (9%). DLTs were nausea (n = 2) and diarrhea (n = 1). 7 pts (13%) had A-related SAEs, including reversible and confounded drug-induced liver injury (Sch B 125 mg and Sch C; 1 each). Disease control rate (DCR) for the total cohort was 36%. Preliminary PK at 150 mg BID suggests adequate coverage for cell kill activity and no drug–drug interaction. Conclusions: The MTD/RP2D was A 150 mg BID (3 d on, 4 d off; treatment d 15–17, 22–24) with DV 1500 mg (d 1 Q4W); safety profile was considered acceptable. Preliminary evidence of antitumor activity was observed. Clinical trial information: NCT02617277. [Table: see text]

scholarly journals First-in-Class, First-in-Human Phase I Study of Selinexor, a Selective Inhibitor of Nuclear Export, in Patients With Advanced Solid Tumors

2016 ◽  
Vol 34 (34) ◽  
pp. 4142-4150 ◽  
Author(s):  
Albiruni R. Abdul Razak ◽  
Morten Mau-Soerensen ◽  
Nashat Y. Gabrail ◽  
John F. Gerecitano ◽  
Anthony F. Shields ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Phase Ii ◽  
Nuclear Export ◽  
Quantitative Polymerase Chain Reaction ◽  
Evaluation Criteria ◽  
Maximum Tolerated Dose ◽  
Nuclear Accumulation ◽  
Advanced Solid Tumors ◽  
Recommended Phase Ii Dose ◽  
Tumor Biopsies

Purpose This trial evaluated the safety, pharmacokinetics, pharmacodynamics, and efficacy of selinexor (KPT-330), a novel, oral small-molecule inhibitor of exportin 1 (XPO1/CRM1), and determined the recommended phase II dose. Patients and Methods In total, 189 patients with advanced solid tumors received selinexor (3 to 85 mg/m2) in 21- or 28-day cycles. Pre- and post-treatment levels of XPO1 mRNA in patient-derived leukocytes were determined by reverse transcriptase quantitative polymerase chain reaction, and tumor biopsies were examined by immunohistochemistry for changes in markers consistent with XPO1 inhibition. Antitumor response was assessed according Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 guidelines. Results The most common treatment-related adverse events included fatigue (70%), nausea (70%), anorexia (66%), and vomiting (49%), which were generally grade 1 or 2. Most commonly reported grade 3 or 4 toxicities were thrombocytopenia (16%), fatigue (15%), and hyponatremia (13%). Clinically significant major organ or cumulative toxicities were rare. The maximum-tolerated dose was defined at 65 mg/m2 using a twice-a-week (days 1 and 3) dosing schedule. The recommended phase II dose of 35 mg/m2 given twice a week was chosen based on better patient tolerability and no demonstrable improvement in radiologic response or disease stabilization compared with higher doses. Pharmacokinetics were dose proportional, with no evidence of drug accumulation. Dose-dependent elevations in XPO1 mRNA in leukocytes were demonstrated up to a dose level of 28 mg/m2 before plateauing, and paired tumor biopsies showed nuclear accumulation of key tumor-suppressor proteins, reduction of cell proliferation, and induction of apoptosis. Among 157 patients evaluable for response, one complete and six partial responses were observed (n = 7, 4%), with 27 patients (17%) achieving stable disease for ≥ 4 months. Conclusion Selinexor is a novel and safe therapeutic with broad antitumor activity. Further interrogation into this class of therapy is warranted.

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