A first-in-human phase I study to evaluate the pan-PI3K inhibitor GDC-0941 administered QD or BID in patients with advanced solid tumors

3501 Background: The PI3K-PTEN-AKT signaling pathway is deregulated in a wide variety of cancers. GDC-0941 is a potent and selective oral inhibitor of the class I PI3K with 3 nM IC50 for the p110-alpha subunit in vitro and 28 nM IC50 in a cell-based pAKT assay and demonstrates broad activity in breast, ovarian, lung, and prostate cancer models. Methods: A Phase I dose escalation study using a 3+3 design was initiated in patients (pts) with solid tumors. GDC-0941 was given on d1, followed by 1 wk washout to study single-dose PK and PD markers. GDC-0941 was then administered qd on a 3 wk on, 1 wk off, schedule. Steady-state PK and PD were evaluated after 1 wk of continuous dosing. A separate concurrent dose-escalation arm with bid dosing was initiated after the third qd cohort. Results: Nineteen pts have been enrolled in 5 successive dose-escalation cohorts in the qd arm with dose levels up to 80 mg daily. Seven pts were enrolled in 2 cohorts in the bid arm at total daily doses of 60 and 80 mg. The most frequently reported drug-related AEs were Grade 1/2 nausea, fatigue, diarrhea, peripheral edema, and dysgeusia; no drug related grade >3 events have been reported. PK data suggest dose-proportional increases in Cmax and AUC. Potential signs of anti-tumor activity have been observed with a soft tissue sarcoma pt on-study for >176 days with stable disease (30 mg qd), an ovarian cancer pt with an on-study 2.8-fold decrease in CA-125 response to normal levels (30 mg bid) and a pt with endometrial cancer with a decrease in tumor FDG-PET uptake (80 mg qd). Conclusions: GDC-0941 is generally well-tolerated with potential signs of anti-tumor activity. Preliminary PK data suggest dose-proportional increases in exposure over the dose levels evaluated. Dose-escalation on both the qd and bid schedules continues with updated data to be presented. [Table: see text]

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Phase I study of bortezomib and oxaliplatin (BOX) in solid tumors: Improved neurotoxicity (NT) profile with lower bortezomib (B) dose

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.12007 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 12007-12007

Author(s):

R. A. Kosloff ◽

J. Wright ◽

P. Ivy ◽

J. Escalon ◽

B. Norwood ◽

...

Keyword(s):

Phase I ◽

Solid Tumors ◽

Dose Escalation ◽

Phase I Study ◽

Major Contributor ◽

Organ Function ◽

Dose Escalation Study ◽

Adequate Organ Function ◽

Dose Levels ◽

Platinum Agents

12007 Background: B inhibits proteasome function and may be synergistic in causing apoptotic death with platinum agents. We were interested in combining B with OX but concerned with dose limiting (DL) NT based on our prior B phase I study [Hamilton et al., JCO 2005]: therefore this Phase I dose-escalation study (alternating increases of B and OX) focusing on NT was planned. Methods: Patients (pts) with metastatic solid tumors, PS 0–2, platinum or taxane naive, no peripheral neuropathy and adequate organ function, received B (D1, 4, 15, 18) and OX (D1, 15) every 28 days in a dose escalation design (see table ). Baseline and monthly assessments were performed by an independent neurologist. Results: 27 (18 gastrointestinal, 3 melanoma, 3 ovarian, 3 others) were accrued; pt characteristics: 14 male/13 female; median age 55 years (range 35–75); 2 median cycles (range 1–10). NT was not DL because it did not occur within the first cycle. Late and limiting NT was observed in levels 2–5 after 2–9 cycles, but serial neurologic evaluations showed reversible NT. With an amended new dose level to lower B to 1.0 mg/m2 (level 6) to avoid late NT, NT was not observed. Of 22 evaluable pts, there were 3 partial responses (ampullary, GE junction, biliary), 6 stable disease, and 13 disease progression by RECIST criteria. Conclusions: biweekly BOX is tolerable at B 1.0 mg/m2 and OX 85 mg/m2 with no DL NT. Additional observations on late NT are ongoing. This suggests B is a major contributor to NT observed in dose levels 2–5 and may potentiate the effects of OX. [Table: see text] [Table: see text]

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Phase I study of ON-01910.Na, a novel cell cycle inhibitor in adult patients with solid tumors

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.13026 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 13026-13026 ◽

Cited By ~ 9

Author(s):

R. C. Donehower ◽

A. Jimeno ◽

J. Li PhD ◽

K. Galvin ◽

F. Anthony ◽

...

Keyword(s):

Cell Cycle ◽

Antitumor Activity ◽

Phase I ◽

Solid Tumors ◽

Dose Escalation ◽

Cross Resistance ◽

Dose Escalation Study ◽

Cell Cycle Inhibitor ◽

Recommended Phase Ii Dose ◽

Dose Levels

13026 Background: ON-1910.Na is a new chemical entity, novel cell cycle inhibitor which arrests cells in G2/M, affects phosphorylation of several regulatory kinases and lacks cross resistance to other standard chemotherapy agents. This is a first-in-man Phase I dose escalation study to determine the dose limiting toxicities, recommended Phase II dose, and pharmacokinetic (PK) profile, and to document any antitumor activity of ON-01910.Na. Methods: Patients had histologically confirmed solid tumors refractory to standard therapy. ON-1910.Na, formulated as a solution in PEG400, was administered as a 2-hour infusion on days 1, 4, 8, 11, 15, and 18 followed by a 10 day observation period for a total of 28 days per cycle. The initial dose was 80 mg and was escalated using an accelerated titration schedule; one patient was treated per cohort until grade 2 toxicity was documented. A dose confirmation cohort of up to 12 patients will be treated at the maximun tolerated dose (MTD). A comprehensive PK study was performed on days 1 and 15 of the first cycle, plus trough samples were collected. Results: Thirteen patients (7F, 6M; ages 46–73) have received 20 cycles. Dose levels of 80, 160, 320, 480, 800, 1280, 2080, and 3120 mg were evaluated in 8 patients, and a further dose of 4370 mg has been evaluated in 5 patients. Toxicities have been anemia (2 G1, 1 G2), leucopenia (1 G1, 1 G2), hyperglycemia (2 G1), elevated AST/ALT (1 G1, 1 G2), nausea (3 G1), diarrhea (3 G1), skeletal pain (5 G1, 1 G2), abdominal pain (2 G1), tumor pain (1 G2), and fatigue (3 G1, 1 G2), and have clustered at the latter 3 dose levels. PK analysis shows increasing ON-1910.Na exposure with increasing doses. ON-1910.Na has a low clearance (13 L/h), long half-life (20 h), distribution in excess of blood volume (58 L) and PK parameters are similar on days 1 and 15. Approximately 3-fold and 5-fold inter-subject variation in ON-1910.Na clearance was observed on days 1 and 15, respectively. No antitumor activity has been documented by standard criteria. Conclusions: Dose escalation is continuing. [Table: see text]

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First-in-human phase I dose-escalation study of the oral selective C-met inhibitor EMD 1204831 in patients with advanced solid tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.3107 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 3107-3107

Author(s):

Hesham M. Amin ◽

Gerald Steven Falchook ◽

Siqing Fu ◽

David S. Hong ◽

Apostolia Maria Tsimberidou ◽

...

Keyword(s):

Phase I ◽

Solid Tumors ◽

Dose Escalation ◽

Cell Surface Receptor ◽

Advanced Solid Tumors ◽

Multiple Dosing ◽

Dose Escalation Study ◽

Tumor Cell Migration ◽

Met Inhibitor ◽

Anti Tumor Activity

3107^ Background: The cell surface receptor tyrosine kinase c-Met and its ligand, the hepatocyte growth factor, are implicated in tumor cell migration, invasion, survival, and proliferation. EMD 1204831 is a novel potent and highly selective reversible, ATP-competitive small molecule c-Met inhibitor. Methods: This is a phase I, first-in-human clinical trial with escalating doses of EMD 1204831 (NCT01110083). The primary objective was to determine the maximum tolerated dose (MTD). Secondary objectives included evaluation of safety, pharmacokinetics (PK), pharmacodynamics (Pd), and preliminary anti-tumor activity. Eligible patients had advanced solid tumors not amenable to standard therapies. Following a classical 3+3 dose-escalation scheme, successive cohorts of patients were treated with twice daily (BID) oral EMD 1204831 in 21-day cycles. Pd markers were evaluated in paired tumor biopsies (phospho-c-Met). Results: Until 31 December 2011, 30 patients were enrolled and treated. The dose was escalated in successive cohorts starting from 50 mg BID up to 1400 mg BID. After first (single) administration, median Cmax and AUC0–12 values increased with dose. At higher doses, a decrease in exposure of EMD 1204831 was noted after multiple dosing, potentially caused by autoinduction of the compound’s metabolism. Further dose escalation was discontinued, and no further patients were enrolled. One dose-limiting toxicity (DLT) of grade (G) 3 pancreatitis, considered as a serious adverse event (AE), was observed at 400 mg BID. No other DLTs or treatment-related serious AEs were observed. The remaining treatment-related AEs of G2 or higher included G3 and G2 lipase elevation (n=1 for each grade), G2 upper abdominal pain (n=2), G2 gastroesophageal reflux disease (n=2), and G2 constipation (n=1). Twenty-five patients (83%) had no drug-related toxicity greater than G1. Of 29 patients evaluable for anti-tumor activity, 3 had stable disease lasting for at least 4 months. Conclusions: Due to potential autoinduction of the compound’s metabolism, dose escalation was discontinued before an MTD was reached. Final safety, PK, and clinical tumor response results will be presented.

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A Phase I, Multi-Center, Dose Escalation Study of Atiprimod in Patients with Refractory or Relapsed Multiple Myeloma (MM).

Blood ◽

10.1182/blood.v106.11.111.111 ◽

2005 ◽

Vol 106 (11) ◽

pp. 111-111 ◽

Cited By ~ 7

Author(s):

Michael Wang ◽

Moshe Talpaz ◽

Sundar Jagannath ◽

Asher Alban Chanan-Khan ◽

Raymond Alexanian ◽

...

Keyword(s):

Phase I ◽

Dose Escalation ◽

Treated Group ◽

Median Number ◽

Maximum Tolerated Dose ◽

Clinical Activity ◽

Dose Escalation Study ◽

M Proteins ◽

Dose Levels

Abstract Atiprimod (N-N-diethl-8, 8-dipropyl-2-azaspiro [4,5] decane-2-propanamine) is an orally bioavailable cationic amphilic compound that inhibited STAT 3 activation in MM cells. It effectively blocked the signaling pathway of interleukin-6, resulting in activation of caspase 3 and apoptosis (Amit-Vazina et al, Br J Cancer, 2005). Atiprimod has also induced cytotoxicity in dexamethasone, doxorubicin, and melphalan resistant MM cell lines (Hamasaki et al, Blood, 2005). Based on these encouraging in vitro data, we initiated a multi-center, phase I trial of atiprimod for patients (pts) with refractory or relapsed MM who had 2 prior lines of therapy and serum creatinine less than 2 mg/dl. Primary objectives were to evaluate the safety of atiprimod in MM pts and to identify the maximum tolerated dose (MTD). Each cycle of treatment consisted of 14 consecutive days of oral atiprimod followed by 14 consecutive days without treatment. A standard phase I dose escalation was used to determine MTD with atiprimod dose levels at 30 mg, 60 mg, 90 mg, 120 mg, and 180 mg. To date, 14 pts from 4 centers have been enrolled with evaluable data in 12 patients. Median age was 60 (range 44–64); median prior lines of therapy were 4 (range 3–7); median duration from initial treatment to registration to this trial was 36 months (range 19–76). Cohorts of 3 patients have been treated at 30, 60, 90,120 mg/day and 2 patients have been enrolled at the 180 mg/day level; no cohorts have been expanded because of dose-limiting toxicity. Median number of cycles received by MM pts was 2 (range 1–5). Common Grade 1 toxicity events included diarrhea, liver enzyme elevation and dyspepsia. There were two Grade 2 toxicity events with 1 neutropenia at the 90 mg/day level and 1 diarrhea at the 120 mg/day level. One pt had Grade 3 transaminase elevation (peak AST 402, ALT 469 units/L, bilirubin 0.5 mg/dl) during the second cycle that resolved on its own during the 14 day period off treatment. Two patients with rapidly rising serum M proteins prior to enrollment had a transient but clear reduction of their M proteins (30% and 80%) after the first 14 days of atiprimod. Two pts at higher dose levels noted subjective improvement in their bone pain. Atiprimod was generally well tolerated in this heavily treated group of MM pts. The MTD has not been reached. Although there has been no response to date, clinical activity is not expected until higher dose levels are evaluated (240 mg/day, 300 mg/day, and 360 mg/day). After the MTD has been established, the study of atiprimod combinations should be considered based on the in vitro assessment of synergy with other active agents.

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DIPG-11. A PHASE I DOSE ESCALATION STUDY OF BXQ-350 IN CHILDREN AND YOUNG ADULTS WITH RELAPSED SOLID TUMORS

Neuro-Oncology ◽

10.1093/neuonc/noaa222.061 ◽

2020 ◽

Vol 22 (Supplement_3) ◽

pp. iii289-iii289

Author(s):

Bhuvana Setty ◽

Timothy Cripe ◽

Mariko DeWire- Schottmiller ◽

Richard Curry ◽

Mohamed AdelBaki

Keyword(s):

Phase I ◽

Solid Tumors ◽

Dose Escalation ◽

Phase I Trial ◽

Objective Response ◽

Antitumor Effects ◽

Serious Adverse Events ◽

Dose Escalation Study ◽

Pediatric Dose

Abstract BXQ-350 is a novel agent composed of the multifunctional, lysosomal activator protein Saposin C (SapC) and dioleoyl- phosphatidylserine (DOPS). BXQ-350 demonstrated antitumor effects in vitro and in vivo. Many tumors, including diffuse intrinsic pontine glioma (DIPG), and cells of tumor vasculature have aberrantly-exposed PS-rich domains on the cell surface. BXQ-350 is an anti-tumor agent in development from Bexion Pharmaceuticals, Inc. that selectively targets tumor cell PS, particularly those translocated to the outer leaflet of the plasma membrane in tumor cells. BXQ-350 activates and participates in various cellular processes, including apoptosis and necrosis, and may also exhibit novel mechanisms leading to cell death that require further investigation. An adult Phase I trial with BXQ-350 completed enrollment in 2019 having dosed 86 recurrent solid tumor patients, including glioblastoma, with only one serious infusion-related reaction. The highest planned dose of 2.4 mg/kg was achieved and seven patients remain on study with multiple cases demonstrating an objective response. A Phase I pediatric dose escalation trial in recurrent solid tumors, including central nervous system (CNS) tumors, also completed enrollment in 2019. The highest planned dose of 3.2 mg/kg was achieved and there have been no BXQ-350 related serious adverse events. Eight patients (7 CNS and 1 non-CNS) completed at least one cycle with one DIPG patient completing cycle five. A pediatric Phase I trial in newly diagnosed DIPG and diffuse midline glioma (DMG) is planned for 2nd quarter 2020.

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A first-in-human phase I study of CYH33, a phosphatidylinositol 3-kinase (PI3K) α selective inhibitor, in patients with advanced solid tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e15645 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e15645-e15645 ◽

Cited By ~ 1

Author(s):

Xiao-Li Wei ◽

Rui-hua Xu ◽

Hongyun Zhao ◽

Yang Zhang ◽

Ben-Yan Zou ◽

...

Keyword(s):

Phase I ◽

Solid Tumors ◽

Dose Escalation ◽

Pik3ca Mutation ◽

Selective Inhibitor ◽

Advanced Solid Tumors ◽

Mutation Status ◽

Grade 3 ◽

Dose Levels ◽

Anti Tumor Activity

e15645 Background: PI3Kα is the only subtype in PI3K family of which activated mutations occur frequently in tumors. CYH33 is a potent PI3Kα–selective inhibitor with anti-tumor activity in xenograft models. An open-label, Phase I dose-escalation & expansion study of CYH33 monotherapy (NCT03544905) is underway in patients (pts) with advanced solid tumors. Methods: This study evaluates the safety, pharmacokinetics (PK), and anti-tumor activity of CYH33 administered daily orally in 28-day cycles until intolerable toxicity or disease progression (PD). Adult pts with advanced solid tumors who have progressed despite standard therapies are enrolled to this trial, and pts with or without PIK3CA mutant are eligible for dose-escalation and pts with PIK3CA mutant are eligible for dose-expansion. Results: As of the cut-off date 20 Dec 2019, 17 pts (median age 47.0 y) were enrolled in the first 6 dose levels (1mg, 5mg, 10mg, 20mg, 40mg and 60mg) of the dose-escalation cohorts, and 3 pts were enrolled in expansion cohort of 40 mg. Cohorts 1 mg to 20 mg were completed without dose-limiting toxicities (DLT), cohort 40mg was completed with 1 DLT (Grade 3 hyperglycemia) out of 6 evaluable pts, and 3 enrolled pts at 60 mg are still in the DLT evaluation. Most frequent treatment-related adverse events (TRAEs) (all grades, ≥ 20%) included hyperglycemia (17 pts, 85%), decreased appetite (5 pts, 25%), diarrhea (4 pts, 20%). Grade≥3 TRAEs were hyperglycemia (8 pts, 40%), nausea (1 pt, 5%) and decreased appetite (1 pt, 5%). Hyperglycemia was generally manageable with anti-hyperglycemic medications. The preliminary PK profile of CYH33 showed dose proportionality across the tested dose levels, half-life (t1/2) was about 20 hours with minimum accumulation, and the maximum concentration (Cmax) achieved 2-4 hours after dosing. Over all, among 15 tumor response evaluable pts, partial response (PR) was observed in 2 pts treated with 40mg (1 colorectal cancer with unknown PIK3CA mutation status, 1 breast cancer with PIK3CA mutant), and stable disease (SD) was observed in 3 pts with unknown PIK3CA mutation status. After the cut-off date, 1 more pt (ovarian cancer with PIK3CA mutation) treated with 40mg achieved PR, so that 2 out of 3 enrolled PIK3CA mutant pts treated with 40mg achieved PR. Conclusions: The first-in-human study of the PI3Kα selective inhibitor CYH33 demonstrated a manageable safety profile, linear PK, and encouraging preliminary anti-tumor activity. CYH33 single agent and in combination with other anti-tumor agents have be planned in future studies. Clinical trial information: 03544905.

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Safety and efficacy of AK112, an anti-PD-1/VEGF-A bispecific antibody, in patients with advanced solid tumors in a phase I dose escalation study.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.2515 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 2515-2515

Author(s):

Jermaine Coward ◽

Anna Rachelle Austria Mislang ◽

Sophia Frentzas ◽

Charlotte Rose Lemech ◽

Adnan Nagrial ◽

...

Keyword(s):

Phase I ◽

Solid Tumors ◽

Dose Escalation ◽

Bispecific Antibody ◽

Advanced Solid Tumors ◽

Antitumor Effects ◽

Dose Escalation Study ◽

Safety And Efficacy ◽

Anti Vegf ◽

Anti Tumor Activity

2515 Background: AK112 is a tetrameric bispecific antibody targeting PD-1 and VEGF-A. Published data suggests that the combination of anti-VEGF-A with immune checkpoint inhibitor (ICI) therapy produces complementary and synergistic antitumor effects. Given the strong correlation between VEGF-A and PD-1 expression in the tumor microenvironment, it is postulated that the simultaneous blockade of these 2 targets by AK112 as a single agent might achieve higher target binding specificity and produce enhanced antitumor activity, with an improved safety profile, compared to the co-administration of anti-PD-(L)1 and anti-VEGF therapies. Here, we present preliminary safety and efficacy data from a dose escalation study of AK112. Methods: A multicenter, phase I, open-label dose escalation and expansion study in advanced solid tumors that are resistant/refractory to standard therapies, began in December 2019 to determine the safety and efficacy of AK112 (0.3 mg/kg to 30 mg/kg) administered IV every 2 weeks (Q2W) using an accelerated titration followed by 3+3+3 dose escalation design. Selected dose escalation cohorts were expanded to a maximum of 18 subjects with selected solid tumor types for further evaluation of safety, pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity, and anti-tumor activity. Pts with prior exposure to ICI were eligible. PD studies examined serum VEGF levels and PD-1 receptor occupancy (RO) on circulating T-cells as an indication of target engagement. Results: As of 13 Jan 2021, 29 pts, median age 60 years [30-76], have received AK112 at doses of 0.3 mg/kg (n = 1), 1.0 mg/kg (n = 3), 3.0 mg/kg (n = 3), 10.0 mg/kg (n = 13), 20.0 mg/kg (n = 8), and 30.0 mg/kg (n = 1) Q2W. Treatment-related adverse events (TRAEs) occurred in 55.2% of pts. G3 TRAEs occurred in 10.3% [3/29] and treatment-related SAEs occurred in 3.4% [1/29] of pts. There was no G4 TRAE. No DLT occurred. TRAEs leading to treatment discontinuation occurred in 6.9% of pts [2/29]. Most frequent TRAEs were arthralgia (17%), diarrhea (14%), rash (10%), and fatigue (10.3%). Of the 17 evaluable pts treated at doses ≥ 3 mg/kg Q2W, the ORR was 23.5% (4/17) and disease control rate (DCR) was 64.7% (11/17). Among the 4 responders, a responder (endometrial ca) had not received prior ICI or bevacizumab, 2 responders (ovarian ca, mesothelioma) had received prior ICI therapy; and a responder (microsatellite stable colorectal ca) was previously treated with bevacizumab. Conclusions: AK112, up to 20 mg/kg Q2W (inclusive), can be given safely to pts and demonstrated encouraging anti-tumor activity with an ORR of 23.5% when dosed ≥ 3 mg/kg Q2W in a pt population with various solid tumors resistant/relapsed to standard therapies. Enrolment is currently ongoing at 30.0 mg/kg Q2W and in dose escalation cohorts selected for expansion. Updated data, including PK, serum VEGF, and RO will be presented. Clinical trial information: NCT04047290.

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