Phase I dose-escalation study of XL147, a PI3K inhibitor administered orally to patients with solid tumors

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 3500-3500 ◽  
Author(s):  
G. Shapiro ◽  
E. Kwak ◽  
J. Baselga ◽  
J. Rodon ◽  
C. Scheffold ◽  
...  
Keyword(s):  
Steady State ◽  
Solid Tumors ◽  
Skin Rash ◽  
Dose Escalation ◽  
Plasma Concentrations ◽  
Safety Data ◽  
Pi3k Pathway ◽  
Dependent Manner ◽  
Dose Escalation Study ◽  
Grade 3

3500 Background: XL147 is a selective inhibitor of Class I PI3K isoforms. In preclinical cancer models XL147 is cytostatic or cytoreductive as monotherapy and enhances the efficacy of targeted agents and chemotherapeutics. This open label, Phase 1 dose escalation study assesses the safety, pharmacokinetics, pharmacodynamics, and efficacy of XL147 in advanced solid tumors. Methods: For each 28 day cycle, patients (pts) receive XL147 on Days 1–21 (21/7) or as a continuous daily dose (CDD). Cycle 1 safety data determine dose-limiting toxicities (DLTs). Tumor response is assessed every 8 weeks. Results: As of December 2008, 39 pts have been treated: 36 on 21/7 across 7 dose levels (30–900 mg) and 3 on CDD at 100 mg. At 900 mg, 2 of 3 pts experienced a DLT of reversible grade 3 rash, and the MTD was established as 600 mg based on 15 pts. Drug-related toxicities included grade 3 skin rash (3 pts), grade 3 arterial thrombosis (1 pt), grade 2 transaminase elevation (1 pt), and grade 1 hyperglycemia (4 pts). XL147 exposure increased with dose from 30–400 mg and was similar from 400–900 mg. XL147 reached steady-state plasma concentrations by Day 15–20. Mean t1/2, z at steady-state ranged from 3.7–6.3 days. Doses ≥400 mg yielded exposures that exceeded the EC90 in xenograft models. A trend suggesting augmented food-induced changes in insulin was evident; however, glucose was minimally affected. XL147 reduced levels of phosphorylated PI3K pathway components in PBMCs, hair, skin, and tumor tissues in an exposure-dependent manner. In 2 pts dosed at the MTD, reductions of ≥70% in PI3K pathway signaling were observed in tumor tissue without compensatory upregulation of MEK/ERK phosphorylation. As of December 2008, 6 pts (3 NSCLC, 1 BCC, 1 NHL, 1 PC) continued on study >6 months including 3 >10 months (NHL, NSCLC, BCC). One pt with hormone refractory PC has sustained a normalization of PSA levels through 5 months. Conclusions: XL147 was generally well tolerated with the MTD for the 21/7 schedule defined as 600 mg. The most common drug-related toxicity was skin rash. Inhibition of PI3K pathway signaling has been demonstrated in tumor and surrogate tissues. Prolonged stable disease has been observed. [Table: see text]

Phase Ib study of MIW815 (ADU-S100) in combination with spartalizumab (PDR001) in patients (pts) with advanced/metastatic solid tumors or lymphomas.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 2507-2507 ◽  
Author(s):  
Funda Meric-Bernstam ◽  
Shahneen Kaur Sandhu ◽  
Omid Hamid ◽  
Anna Spreafico ◽  
Stefan Kasper ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Checkpoint Inhibitors ◽  
Dose Schedule ◽  
Dependent Manner ◽  
Antitumor Effects ◽  
Dose Escalation Study ◽  
Phase Ib ◽  
Grade 3 ◽  
Sting Pathway

2507 Background: MIW815 (ADU-S100) is a novel synthetic cyclic dinucleotide that activates the STimulator of INterferon Genes (STING) pathway impacting tumor cells, tumor microenvironment, vasculature, tumor-associated fibroblasts, and priming APC and CD8+ T cells. Spartalizumab is a humanized IgG4 mAb that blocks the binding of PD-1 to PD-L1/2. Preclinical data support synergistic antitumor effects when MIW815 (ADU-S100) is combined with checkpoint inhibitors. Methods: In this Phase Ib dose escalation study, pts with advanced/metastatic solid tumors or lymphoma received MIW815 (ADU-S100) (intratumoral injections [50–800 µg] either weekly [3 weeks on/1 week off] or Q4W) and spartalizumab (400 mg IV Q4W). Injected and non-injected tumor biopsies were obtained at baseline and on treatment. Primary objectives are to determine safety and identify a dose/schedule for future studies. Preliminary activity, pharmacokinetics (PK), and pharmacodynamics (PD) are also being explored. Results: As of Jan 11, 2019, 66 pts (median age: 61 y) with various solid tumors or lymphomas have been treated. Treatment was discontinued in 49 pts (74%) due to disease progression (n = 28), pt/physician decision (n = 18), AE (n = 2), or death (n = 1). No DLTs were reported during the first cycle at any dose level. Most common (≥5 pts) treatment-related AEs (TRAEs) were injection site pain (12%), pyrexia (11%), and diarrhea (9%). Grade 3/4 TRAEs (in ≥2 pts) were increased AST and ALT (3% each). Serious TRAEs were pyrexia (3%), increased amylase, increased lipase, diarrhea, fatigue, hyperthyroidism, partial seizures, dyspnea, and pneumonitis (all 2%). Partial responses in pts with PD-1–naive TNBC and PD-1–relapsed/refractory melanoma have been observed. MIW815 (ADU-S100) plasma exposure generally increased in a dose-dependent manner with a rapid terminal half-life. Response data, PK and PD analyses will be presented. Conclusions: Thus far, MIW815 (ADU-S100) + spartalizumab has demonstrated antitumor activity in PD-1–naive TNBC and PD-1–relapsed/refractory melanoma. The combination is well tolerated, with no DLTs reported to date. The MTD has not been reached and dose escalation is ongoing. Clinical trial information: NCT03172936.

A phase I open-label, dose-escalation study of intravenous ascorbic acid in combination with gemcitabine and erlotinib in patients with metastatic pancreatic cancer.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 323-323 ◽  
Author(s):  
Susan Joy Littman ◽  
Daniel Monti ◽  
Andrew Newberg ◽  
Anthony Bazzan ◽  
Madhavan V. Pillai ◽  
...  
Keyword(s):  
Ascorbic Acid ◽  
Steady State ◽  
Phase I ◽  
Dose Escalation ◽  
Safety Data ◽  
Open Label ◽  
Dose Escalation Study ◽  
First Line Therapy ◽  
Grade 3 ◽  
Vit C

323 Background: IV ascorbic acid (vit c) is a prodrug for steady state formation of ascorbate radical (Asc·-) in the extracellular space resulting in sustained production of H2O2 leading to selective killing of tumor cells by a pro-oxidative mechanism. In preclinical models of panc cancer pharmacologic concentrations of Asc·- with gem resulted in a synergistic cytotoxic response. We conducted a Phase I dose escalation study of IV ascorbic acid with gem plus erlotinib chemo as first line therapy in panc cancer. Methods: Patients with adv panc cancer were enrolled using a standard 3+3+3 design to assess the safety and pharmacology of IV vit c in combo with gem and erlotinib. Cohort 1 received 50 g IV vit c and subsequent cohorts were escalated by 25 g to a final dose of 100 g. Pts were given 3 infusions of vit c per week on separate days for 8 w (1 cycle). IV gem was given on day 1 (1000 mg/m2) and weekly for 7 w followed by a rest week. Oral erlotinib (100 mg) was given daily for 8 w. Trt continued until disease progression or toxicity. Steady state ascorbate PK was assessed in cohorts 2 and 3. AEs were determined using NCI CTCAE v3.0. Tumor responses were assessed per RECIST. Results: Of 14 pts enrolled, 9 or 3 per cohort completed the study. Median age was 64 years. 5 pts did not complete trt (2 discontinued, 3 died). 9 pts completed at least 24 ascorbic acid trts and 1 cycle of gem/erlotinib therapy. There were 24 AEs. These included 15 non-serious AEs and 8 SAEs. The most frequent AEs were grade 1/2 thrombocytopenia. Other grade 1/2 events included anemia, hyperglycemia, abd discomfort, ascites and infection. SAEs: 2 grade 3 heme, 1 grade 3 GI, 1 grade 3 infectious and 2 grade 4 thrombosis. Plasma asc levels were 25.3 - 31.9 mm/L for pts receiving the 100g dose. 8 of the 9 pts had a reduction in the panc primary with 1 pt having no change at 8 w. For non-target lesions, 2 had PD and 7 had SD per RECIST. Conclusions: Overall safety data do not reveal AEs other than those expected in patients with metastatic panc cancer and/or treatment with gem and erlotinib. Addition of IV ascorbic acid did not increase toxicity. Preliminary efficacy results are encouraging. A phase II study is planned.

A Phase I/II, Dose-Escalation Study of Daratumumab, A CD38 Mab in Patients with Multiple Myeloma – Preliminary Safety Data

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1873-1873 ◽  
Author(s):  
Peter Gimsing ◽  
Torben Plesner ◽  
Hareth Nahi ◽  
Henk Lokhorst ◽  
Marie-Louise Valentin ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Dose Escalation ◽  
Safety Profile ◽  
Treatment Options ◽  
Dose Range ◽  
Safety Data ◽  
Dose Escalation Study ◽  
Full Dose ◽  
Grade 3 ◽  
Trial Drug

Abstract Abstract 1873 Background: Patients with multiple myeloma (MM) relapsed or refractory to current treatment options and ineligible for ASCT have a poor prognosis. Therefore new treatment options are highly needed for this patient population. Malignant MM cells exhibit very strong CD38 surface expression. Daratumumab is a human CD38 antibody with broad spectrum killing activity. Daratumumab mediates MM cell death via antibody dependent cellular cytotoxicity, complement dependent cytotoxicity and apoptosis. Daratumumab has been shown to inhibit growth of CD38-expression tumor cells in SCID mouse xenografts. We report the preliminary safety results from the ongoing first in man dose-escalation study (clin.trial.gov. NCT00574288). Methods: Patients (age > 18 yrs) ineligible for ASCT and relapsed or refractory to at least two different prior therapies receive 7 full and 2 pre-dose infusions of daratumumab (1st pre-dose day 1, 1st full dose day 2, 2nd pre-dose day 21, 2nd full-dose day 22 and thereafter weekly full-dose daratumumab). The study design encompasses a classic 3 + 3 dose escalation with the possibility to limit exposure to 1 patient in the first 2 cohorts pending safety data. The dose range is from 0.005 mg/kg to 24 mg/kg. The primary objective is to establish the safety profile and secondary objectives are to establish MTD and evaluate the efficacy. An independent Data Monitoring Committee evaluates the safety data for each cohort before dose-escalation. Results: Until May 31st, 2011 safety data for 20 patients, including dose range from 0.005 mg/kg up to 2 mg/kg cohort, were collected. Median age 62 yrs (42–76), F/M: 7/13, stage of MM (ISS): 1: 5 patients; 2: 9 patients; 3: 5 patients and 1 unknown. The most common AEs reported across all cohorts are pyrexia (35%), free hemoglobin (25%), anemia (25%), proteinuria (25%), cough (15%), dizziness (10%), flushing (10%), influenza-like-illness (10%), nausea (10%) hypo/hypertension (10%/10%), thrombocytopenia (10%), hemolysis (15%), lymphopenia (10%), arthralgia (10%), abdominal pain (10%) and chest pain (10%). Five SAE were assessed as related to daratumumab. One patient had anemia grade 3 and thrombocytopenia grade 4, one patient experienced cytokine release syndrome grade 2 and based on these DLT events 3 more patients were enrolled in the 0.1 mg/kg and 1.0mg/kg cohorts, one patient experienced a grade 3 bronchospasm 40 hours after end of trial drug infusion and one patient had AST elevation. All patients recovered after relevant treatment. Since implementation of relevant pre-medication and dilution of trial drug no severe infusion related AEs have been reported. The MTD has not been reached at the cut-off time point for this evaluation. Efficacy evaluation is ongoing and preliminary data will be presented at the meeting. Conclusion: Daratumumab has a favorable safety profile as monotherapy in patients with multiple myeloma in doses up to and including 2 mg/kg. The dose-escalation is ongoing and updated safety data will be presented at the meeting. When the MTD is established, an extension study with daratumumab as monotherapy will be conducted. Disclosures: Plesner: Genmab A/S: Consultancy. Lokhorst:Genmab: Consultancy. Valentin:Genmab A/S: Employment. Lisby:Genmab A/S: Employment. Richardson:Genmab: Consultancy.

Phase I dose escalation study of the anti-IGF-1R monoclonal antibody CP-751,871 in patients with refractory solid tumors

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3586-3586 ◽  
Author(s):  
P. Haluska ◽  
H. Shaw ◽  
G. N. Batzel ◽  
L. R. Molife ◽  
A. A. Adjei ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Receptor Internalization ◽  
Pharmacokinetic Analysis ◽  
Adrenocortical Cancer ◽  
Dose Escalation Study ◽  
Multiple Tumor ◽  
Grade 3

3586 Background: The insulin-like growth factor 1 receptor (IGF-IR), a tyrosine kinase, and its ligands (IGF-I & -2) are upregulated in many human tumors (e.g., breast, prostate, colon and non-small cell lung cancer) and enhance proliferative and prosurvival signaling. Inhibition of IGF-IR activation in tumor models suppresses tumor growth and increases tumor sensitivity to chemotherapy, supporting the development of agents targeting IGF-IR. CP-751,871 is a potent, highly specific, fully humanized, monoclonal antibody that inhibits IGF-IR autophosphorylation and induces receptor internalization. Methods: A Phase I dose escalation study was initiated to define the safety and tolerability, and to characterize the pharmacokinetic properties of CP-751,871 in patients with advanced solid tumors refractory to standard therapies. Results: Following informed consent and screening, a total of 24 patients with refractory solid tumors (e.g. colorectal, NSCLC, sarcoma and prostate cancer; 1–6 previous regimens) were enrolled. Patients received 3 to 20 mg/kg of CP-751,871 by IV infusion on Day 1 of 3-week cycles in four dose-escalation cohorts of 3 patients. No dose limiting toxicities were identified and the maximum feasible dose (MFD) cohort of 20 mg/kg was extended with 12 additional patients. No higher than grade 3 CTCAE v3.0 toxicities, attributed to study drug, have been so far reported. Grade 3 toxicities, all reported in patients dosed with 20 mg/kg of CP-751,871, are increased GGT (4%) and fatigue (4%). Grade 2 toxicities include: anorexia (7%), diarrhea (7%), increased GGT (4%), hyperglycemia (4%), fatigue (4%), increased urinary frequency (4%), nausea (4%), increased ALT (4%) and increased AST (4%). Pharmacokinetic analysis is currently ongoing. No objective responses were observed. At the MFD, patients received a median of 4 cycles (1–16). Three patients were stable for > 6 months and one patient, currently at cycle 16, remains on study. An additional cohort of 12 adrenocortical cancer patients is under evaluation. Conclusions: These data indicate that CP-751,871 is safe and well tolerated. Due to its good safety profile, CP-751,871 may constitute a suitable targeted agent to use in combination with approved therapies in multiple tumor types. No significant financial relationships to disclose.

Final results: A dose escalation phase I study of ARQ 197, a selective c-Met inhibitor, in patients with metastatic solid tumors

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 3548-3548 ◽  
Author(s):  
T. Mekhail ◽  
T. Rich ◽  
L. Rosen ◽  
F. Chai ◽  
Z. Semic-Suka ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Safety Profile ◽  
Safety Data ◽  
Dose Escalation Study ◽  
Tumor Cell Migration ◽  
Drug Concentrations ◽  
Arq 197 ◽  
Favorable Safety

3548 Background: ARQ 197 is a selective, non-ATP competitive inhibitor of c-Met, a receptor tyrosine kinase implicated in tumor cell migration, invasion, and proliferation. Methods: This phase I dose escalation study enrolled patients (pts) with metastatic solid tumors to determine the drug's safety profile, maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), pharmacokinetics (PK), and preliminary antitumor activity. Dose escalation followed an accelerated titration design and was modified to the traditional escalation design (3+3 pts) once grade 2 toxicity was observed. ARQ 197 was initially administered orally twice daily (BID) for 2 weeks followed by 1 week off and then modified to evaluate continuous BID dosing based on favorable safety data. Intra-patient dose-escalation was allowed in this study. Additional pts were enrolled and treated at the 360 mg bid continuous dose, which was determined to be the RP2D in another phase I clinical trial. Results: To date, 65 pts (38 male/27 female; median age 61; 9 colon/colorectal, 8 renal cell carcinoma/kidney, 6 ovarian, 6 sarcoma, 5 lung cancer and 31 others) have been treated at 11 dose levels (10 mg bid to 360 mg bid). All treated pts achieved plasma drug concentrations significantly above in vitro IC50 values. The most common drug-related adverse events (AEs) were fatigue (18.5%) and nausea (12.3%). One case each of the following drug-related serious AEs were reported in 4 pts: anemia, leukopenia, neutropenia, thrombocytopenia, dehydration, liver failure, abdominal pain, nausea, and vomiting. Three pts with neuroendocrine, prostate, or testicular cancer achieved a partial response (PR), 32 demonstrated stable disease (SD) and 13 progressed. The 3 PR pts were initially treated at 10, 40 or 90 mg BID respectively. Their doses were escalated to 50, 70, or 120 mg BID respectively after 18 to 33 weeks on treatment. An overall response rate of 6.3% and a disease control rate (CR+PR+SD) of 72.9% were demonstrated among 48 pts who are evaluable for efficacy. Conclusions: ARQ 197 has demonstrated a favorable safety profile up to the dose of 360 mg bid. Preliminary evidence of anti-cancer activity was observed. Final study data on drug safety, PK and efficacy will be presented. [Table: see text]

Phase Ib trial of combining aldoxorubicin plus doxorubicin.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2550-2550
Author(s):  
Kamalesh Kumar Sankhala ◽  
Sant P. Chawla ◽  
Victoria S Chua ◽  
Doris Quon ◽  
Allison Bonk ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Single Agent ◽  
Safety Data ◽  
Tumor Xenograft ◽  
Fixed Dose ◽  
Hematologic Toxicity ◽  
Open Label ◽  
Dose Escalation Study ◽  
Best Response ◽  
Grade 3

2550 Background: Aldoxorubicin is a novel drug that covalently binds to albumin in the circulation with release in low pH environments. Preclinical studies in pancreatic and ovarian tumor xenograft models demonstrated that aldoxorubicin plus doxorubicin administered at 50% of their MTD provided complete and prolonged tumor remission in these models with less toxicity than each drug administered at their MTD. We evaluated the toxicity profile of a fixed dose of doxorubicin and escalating doses of aldoxorubicin in subjects with advanced solid tumors. Methods: Phase 1b open label, dose-escalation study of aldoxorubicin administered at either 175, 240 or 320 mg/m2 (130, 180, or 240 mg/m2 doxorubicin equivalents) iv + 35 mg/m2doxorubicin iv, both on Day 1 of 21 day cycles, for up to 8 cycles. The MTD is the dose level immediately below where 2/6 subjects experience a dose limiting toxicity (DLT) , or the maximum dose of 320 mg/m2aldoxorubicin. Additional subjects may be enrolled at the MTD to provide more safety data. Results: 10 subjects have been treated as of January 21, 2013. No DLT was observed and the MTD was defined as 320 mg/m2 aldoxorubicin and 35 mg/m2 doxorubicin iv administered on Day 1 of 21 day cycles. A median of 4.5 cycles have been received. 3/10 subjects were terminated due to either progressive disease (2) or death (1). No subject was terminated due to an adverse event. Grade 3 or 4 neutropenia was seen at all dose levels (8/10 subjects). 4/10 subjects exhibited grade 3 or 4 thrombocytopenia and 3/10 subjects had grade 3 or 4 anemia. Neutropenic fever occurred in 3/10 subjects. Other grade 3/4 adverse events seen in 2 or fewer subjects included fatigue, increased liver enzymes and dehydration. No significant mucositis or cardiotoxicity was observed. At this time the best response has been stable disease in 6/10 subjects and a partial response in 1 subject (malignant fibrous histiocytoma). Conclusions: The combination of aldoxorubicin (320 mg/m2)) + doxorubicin (35 mg/m2) can be safely administered to subjects with solid tumors. Hematologic toxicity is common and can be controlled with growth factors. The dose of aldoxorubicin is 90% of the MTD of aldoxorubicin administered as a single agent. Thus, doxorubicin does not appear to add to the toxicity of this combination. Clinical trial information: NCT01673438.

Phase I, dose-escalation study of the investigational drug TAK-733, an oral MEK inhibitor, in patients (pts) with advanced solid tumors.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2528-2528 ◽  
Author(s):  
Alex A. Adjei ◽  
Patricia LoRusso ◽  
Antoni Ribas ◽  
Jeffrey Alan Sosman ◽  
Anna C. Pavlick ◽  
...  
Keyword(s):  
Steady State ◽  
Solid Tumors ◽  
Peripheral Blood ◽  
Human Study ◽  
Mek Inhibitor ◽  
Investigational Drug ◽  
Advanced Solid Tumors ◽  
Post Dose ◽  
Dose Escalation Study ◽  
Grade 3

2528 Background: This first-in-human study evaluated the safety, pharmacokinetics (PK), pharmacodynamics (PD), MTD, and efficacy of TAK-733 – an oral, selective, allosteric inhibitor of MEK1/2 – in pts with advanced solid tumors (NCT00948467; completed study). Methods: Eligibility: age ≥18 y; ECOG PS 0–2; evaluable tumors. Pts received escalating doses of TAK-733 QD in a modified 3+3 design for 21 d in a 28-d cycle to determine the MTD based on DLTs in cycle 1. Plasma (PK) and peripheral blood samples (PD: pERK reduction in PBMCs) were obtained pre-dose (d 1, 8, 15, 21) and post-dose (d 1, 21) in cycle1. Results: 51 pts (median age 58 y; 51% M) received escalating doses of TAK-733 (0.2–22 mg; median 2 cycles, range 1–11 [5 pts ≥6 cycles]). 4 pts had DLTs: grade 3 acneiform dermatitis, 1 each at 11.8 and 16mg; grade 3 pustular rash and grade 2 rash/stomatitis (qualifying as a DLT) at 22mg, leading to the 16 mg dose being selected as MTD. 45 pts (88%) had a drug-related AE; most frequent was acneiform dermatitis (47%). 10 pts (20%) had a grade ≥3 drug-related AE; most frequent were creatine phosphokinase increase and acneiform dermatitis (each n=3, 6%). 7 pts discontinued due to AEs. TAK-733 exhibited a moderately fast absorption with a median Tmax of 3 hr. Steady-state exposure of TAK-733 (0.2–22mg) did not increase in a dose proportional manner based on the power model analysis. The mean terminal t1/2 (11.8, 16, and 22 mg) was 43 hr. Overall mean accumulation ratio was 3.5 following QD dosing for 21 d. On d 21, Emax of blood pERK modulation was 56–99%, and time-averaged modulation over the dosing interval at steady-state was 76–98% at MTD. This range correlates well to the 76–89% for pERK modulation associated with maximal efficacy in xenograft models. 1 pt (16 mg) with melanoma (BRAF L597R) had a confirmed partial response after 4 cycles (treated for 9 cycles). 15 pts had a best response of stable disease (4–11.7 months in 6 pts). Conclusions: From preliminary data, TAK-733 appears generally well tolerated, pharmacodynamically active and shows signs of anti-tumor activity in pts with advanced solid tumors. MTD was associated with significant pERK inhibition in peripheral blood. Clinical trial information: NCT00948467.

Phase I dose escalation study of continuous oral dosing of OSI-906, an insulin like growth factor-1 receptor (IGF-1R) tyrosine kinase inhibitor, in patients with advanced solid tumors

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 2559-2559
Author(s):  
C. R. Lindsay ◽  
E. Chan ◽  
T. R. Evans ◽  
S. Campbell ◽  
P. Bell ◽  
...  
Keyword(s):  
Growth Factor ◽  
Tyrosine Kinase ◽  
Dose Escalation ◽  
Kinase Inhibitor ◽  
Plasma Concentrations ◽  
Median Number ◽  
Insulin Like Growth Factor ◽  
Dose Escalation Study ◽  
Molecule Inhibitor ◽  
Grade 3

2559 Background: OSI-906 is a potent small molecule inhibitor of IGF-1R, a receptor tyrosine kinase activated by insulin like growth factor, which is overexpressed in numerous malignancies and implicated in resistance to chemotherapy. Methods: Patients with advanced cancer entered escalating dose cohorts of OSI-906. Study objectives included assessment of: safety; determination of MTD; pharmacokinetics (PK), pharmacodynamics (PD) including IGF-1R levels in peripheral blood cells; and tumor response (RECIST). Results: To date, 32 pts have been treated (22M/10F, median age 62y) at 10, 20, 40, 75, 150, and 300 mg QD and at 20, 40 mg and 75 mg BID. Median number of weeks on trial was 6 (range 0–44). No DLTs have been observed. Hyperglycemia (5/20 pts) related to OSI-906 was transient and mild (grade 1 only). In addition to hyperglycemia, grade 1–2 nausea and vomiting (5/20 pts) were the most frequent related adverse events (AEs). There was grade 3 elevated lipase in 1 pt. At doses of 10–150 mg, OSI-906 exhibited linear PK, median terminal t1/2 ranged from 2.18–4.30 hr, AUC0-inf from 284–10200 ng.hr/mL, and Cmax 76.6–1440 ng/mL. There was no relationship between glucose or insulin levels and OSI-906 plasma concentrations. Stable disease > 12 weeks was seen in 7/20 pts (range 12–34 weeks), including 1 pt each with thymic (27 w), adrenocortical (28w), and colorectal (34w) cancer. PD data on IGF-1R phosphorylation will be presented. Conclusions: Plasma concentrations of OSI-906 achieved in this trial exceed concentrations required for antitumor efficacy in preclinical models. PD target modulation and preliminary anti-tumor activity have been observed. It is interesting to note that clinically meaningful hyperglycemia has yet to occur. Minimal toxicity was observed and further dose escalation is in progress. [Table: see text]

A phase lb, open-label, multicenter, dose-escalation study of the oral pan-PI3K inhibitor BKM120 in combination with the oral MEK1/2 inhibitor GSK1120212 in patients (pts) with selected advanced solid tumors.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3003-3003 ◽  
Author(s):  
Philippe Bedard ◽  
Josep Tabernero ◽  
Razelle Kurzrock ◽  
Carolyn D. Britten ◽  
Anastasios Stathis ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Plasma Concentrations ◽  
Oral Intake ◽  
Maximum Tolerated Dose ◽  
Clinical Activity ◽  
Open Label ◽  
Dose Escalation Study ◽  
Grade 3 ◽  
Recommended Phase Ii Dose ◽  
Bayesian Logistic Regression

3003 Background: MAPK and PI3K/AKT signaling pathways regulate proliferation, differentiation and cell death in human cancers. Known interaction between the 2 pathways provides the rationale for combining both inhibitors in a phase I study. Methods: The objective is to determine the maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D) for oral, daily administered, BKM120 + GSK1120212, mainly in pts with tumors with RAS/RAF mutations (mt). A Bayesian logistic regression model with overdose control guides the dose escalation of the treatment. Secondary objectives include safety, tolerability, PK and efficacy. Results: As of 22.09.11, 49 pts were treated with BKM120 + GSK1120212 as follows: 30mg + 0.5mg, 60mg + 0.5mg, 60mg + 1.0mg, 60mg + 1.5mg, 60mg + 2.0mg, 70mg + 1.5mg, 80mg + 1.0mg, 80mg + 1.5mg. 6 pts had dose-limiting toxicities (DLTs); all were reversible. Grade 3 DLTs were: 3 x stomatitis, 1 x dysphagia, 1 x LVEF decrease, 1 x CK increase, 1 x nausea, 1 x anorexia, 1 x decreased oral intake. MTD and/or RP2D for the combination have not been reached. Most common adverse events (AEs) (>25%), all grades and causality, were dermatitis acneiform, diarrhea (51% each); nausea (41%); vomiting (37%); rash (33%); asthenia (31%); CK increase, decreased appetite, pyrexia or stomatitis (29% each) and hyperglycemia (27%). There were 4 on-treatment deaths unrelated to treatment. AEs led to treatment discontinuation, 17 pts (35%) and interruptions/dose reductions, 25 pts (51%). Apparent steady-states of BKM120 and GSK1120212 were reached by day 28. Plasma concentrations of BKM120 in combination with GSK1120212 were lower than for monotherapy. Exposure to GSK1120212 with BKM120 was similar to that observed in monotherapy studies. 3 confirmed partial responses have been observed in pts with KRAS mt ovarian cancer; 2 lasting >9 months. 2 patients with BRAF mt melanoma, who had previously progressed on BRAF inhibitors, had stable disease, for 1 of whom treatment is still ongoing in cycle 6. Conclusions: BKM120 and GSK1120212 can be safely combined. Signs of clinical activity have been seen in pts with RAS/RAF mt tumors.

Phase I dose-escalation study of AZD7762 alone and in combination with gemcitabine in Japanese patients with advanced solid tumors.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3045-3045 ◽  
Author(s):  
Takashi Seto ◽  
Taito Esaki ◽  
Fumihiko Hirai ◽  
Shuji Arita ◽  
Kaname Nosaki ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Troponin T ◽  
Geometric Mean ◽  
Japanese Patients ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Dose Escalation Study ◽  
Primary Tumor Site ◽  
Grade 3

3045 Background: AZD7762, a potent Chk1/Chk2 inhibitor, has been shown to enhance the antitumor activity of gemcitabine in xenograft models (Zabludoff SD et al. Mol Cancer Ther 2008;7:2955–66). Methods: This open-label dose-escalation study evaluated the safety, pharmacokinetics (PK), and preliminary efficacy (RECIST) of AZD7762 alone and in combination with gemcitabine in Japanese patients (pts) with advanced solid tumors (NCT00937664). Pts received AZD7762 iv alone on days 1 and 8 of a 14-day cycle (Cycle 0), followed by AZD7762 plus gemcitabine 1000 mg/m2 on days 1 and 8 of 21-day cycles, in sequential ascending AZD7762 dose cohorts. Results: 20 pts (mean age 60 years) received AZD7762 at doses of 6 (n=3), 9 (3), 21 (6), and 30 mg (8). The most common primary tumor site was lung (n=14). All pts had received ≥1 prior chemotherapy and 18 had metastatic disease. Dose-limiting toxicities (DLTs) occurred in two of six evaluable pts (both 30 mg cohort): one, grade 3 (CTCAE, v3.0) elevated troponin T (Cycle 0; AZD7762 monotherapy); one, neutropenia, thrombocytopenia, and elevated AST and ALT (Cycle 1; combination therapy). Thus, the 30 mg dose was regarded as non-tolerable. DLTs resolved following treatment discontinuation. The most frequently reported adverse events (AEs) in Cycle 0 (AZD7762 monotherapy) were bradycardia (50%), hypertension (25%) and fatigue (15%). Overall, the most common AEs were bradycardia (55%), neutropenia (45%), and hypertension, fatigue, and rash (30% each). AEs grade ≥3 were reported in 11 pts, the most common being neutropenia (45%) and leukopenia (25%). No pt died due to an AE. AZD7762 exposure (Cmax, AUC) increased in an approximately linear manner. Gemcitabine did not appear to affect AZD7762 PK. Arithmetic mean t½ and geometric mean CL of AZD7762 across the dose groups were 16.1–19.4 h and 22.0–32.7 L/h, respectively during the monotherapy cycle, and 15.6–18.3 h and 21.1–24.4 L/h, respectively in combination with gemcitabine. There were no objective responses; five pts (all lung cancer) had stable disease. Conclusions: The maximum tolerated dose of AZD7762 in combinationwith gemcitabine 1000 mg/m2 was determined as 21 mg in Japanese pts.

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