scholarly journals Phase Ib dose-escalation study of the hypoxia-modifier Myo-inositol trispyrophosphate in patients with hepatopancreatobiliary tumors

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Marcel A. Schneider ◽  
Michael Linecker ◽  
Ralph Fritsch ◽  
Urs J. Muehlematter ◽  
Daniel Stocker ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Tumor Hypoxia ◽  
Maximum Tolerated Dose ◽  
Vascular Normalization ◽  
Treatment Results ◽  
Dose Escalation Study ◽  
Phase Ib ◽  
Disease Stabilization ◽  
Angiogenic Markers ◽  
Dose Levels

AbstractHypoxia is prominent in solid tumors and a recognized driver of malignancy. Thus far, targeting tumor hypoxia has remained unsuccessful. Myo-inositol trispyrophosphate (ITPP) is a re-oxygenating compound without apparent toxicity. In preclinical models, ITPP potentiates the efficacy of subsequent chemotherapy through vascular normalization. Here, we report the results of an unrandomized, open-labeled, 3 + 3 dose-escalation phase Ib study (NCT02528526) including 28 patients with advanced primary hepatopancreatobiliary malignancies and liver metastases of colorectal cancer receiving nine 8h-infusions of ITPP over three weeks across eight dose levels (1'866-14'500 mg/m2/dose), followed by standard chemotherapy. Primary objectives are assessment of the safety and tolerability and establishment of the maximum tolerated dose, while secondary objectives include assessment of pharmacokinetics, antitumor activity via radiological evaluation and assessment of circulatory tumor-specific and angiogenic markers. The maximum tolerated dose is 12,390 mg/m2, and ITPP treatment results in 32 treatment-related toxicities (mostly hypercalcemia) that require little or no intervention. 52% of patients have morphological disease stabilization under ITPP monotherapy. Following subsequent chemotherapy, 10% show partial responses while 60% have stable disease. Decreases in angiogenic markers are noted in ∼60% of patients after ITPP and tend to correlate with responses and survival after chemotherapy.

PX-171–006: Phase Ib multicenter dose escalation study of carfilzomib (CFZ) plus lenalidomide (LEN) and low-dose dexamethasone (loDex) in relapsed and refractory multiple myeloma (MM): Preliminary results

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 8541-8541
Author(s):  
R. Niesvizky ◽  
W. Bensinger ◽  
M. Vallone ◽  
A. Gutierrez ◽  
L. Kunkel
Keyword(s):  
Dose Escalation ◽  
Low Dose ◽  
Stem Cell Transplant ◽  
Single Agent ◽  
Maximum Tolerated Dose ◽  
Cell Transplant ◽  
Dose Escalation Study ◽  
Phase Ib ◽  
Dose Levels ◽  
Dose Limiting Toxicity

8541 Background: CFZ is a highly specific proteasome inhibitor with single agent activity in relapsed/refractory MM (ASH 2008). The purpose of this study is to evaluate the safety and activity of CFZ in combination with LEN and loDex. Methods: This phase Ib trial evaluates 4 dose levels (≥ 3 pts each) to define the maximum tolerated dose (MTD) of CFZ/LEN/loDex in relapsed/refractory MM pts who failed 1–3 prior therapies, including prior LEN or bortezomib (BTZ). CFZ IV 15- 20 mg/m2 (d1,2,8,9,15,16), LEN 10–20 mg po (d1–21) and loDex 40 mg po (d1, 8, 15, 22) in 28-day cycles (C). An additional 10–15 pts will be evaluated at the highest dose level reached. Dose limiting toxicity (DLT) has been defined as grade (G) ≥ 3 non- hematologic; G4 neutropenia for > 7d and/or neutropenic fever; G4 thrombocytopenia > 7d or G3-G4 thrombocytopenia in association with bleeding. Overall response (CR/sCR, VGPR/PR) is assessed by IWG criteria, with secondary assessment by modified EBMT criteria which includes MR. Results: 11 pts have been enrolled. 8/11 are evaluable for response and toxicity. Median prior lines of therapy was 2 (range 2–3). Prior therapies included DEX (8/8), BTZ (6/8), LEN (7/8), alkylators (6/8), anthracyclines (5/8), stem cell transplant (5/8), and thalidomide (1/8); 6/8 pts had received both LEN and BTZ. MTD has not yet been reached after the first 2 dose cohorts. No drug related SAEs or G3/4 treatment emergent AEs were reported. Responses to date with a median of 2 C (range 1–4) are shown below. Responses were rapid and occurred within the first 28-day cycle. Conclusions: CFZ/LEN/loDex in combination was well tolerated in the first 2 cohorts. There have been no myleosuppressive or renal DLTs. The combination has achieved early encouraging responses in pts who had failed both LEN and BTZ at doses well below the single agent MTD of either LEN or CFZ. Dose escalation is ongoing. Updated data will be presented at the meeting. [Table: see text] [Table: see text]

Phase I dose-escalation study of ZK 304709, an oral multi-target tumor growth inhibitor (MTGI), administered for 14 days of a 28-day cycle

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2076-2076 ◽  
Author(s):  
S. Ahmed ◽  
R. Molife ◽  
H. Shaw ◽  
W. Steward ◽  
A. Thomas ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Tyrosine Kinases ◽  
Oral Delivery ◽  
Growth Inhibitor ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Dose Escalation Study ◽  
Cycle Arrest ◽  
Disease Stabilization ◽  
Dose Levels

2076 Background: ZK 304709 is a novel oral MTGI that induces cell cycle arrest and inhibits tumour angiogenesis by selectively inhibiting Cyclin Dependent Kinases (CDKs) 1, 2, 4, 7 and 9,VEGF-R 1, 2 and 3, and PDGF-Rβ tyrosine kinases. Methods: Adult patients (pts) (WHO PS ≤2) with a histologically or cytologically confirmed solid tumor, resistant or refractory to conventional therapy, were eligible. ZK304709 was administered orally, once daily, at a 15 mg starting dose, on days 1–14 of a 28-day cycle, then escalated by 33–100% depending on incidence of drug-related toxicity ≥ grade (gr) 2 (CTC v2.0). At least 3 pts were treated at each dose level. The primary objective was to identify the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT). Secondary objectives were to determine the tolerability, pharmacokinetic (PK) profile, and preliminary efficacy. Results: Interim results were available for 24 pts (19 M/5 F; median age 56.5) at 5 dose levels (15–120 mg qd). Pts received a median of 2 cycles (range 0–10). Common drug related toxicities were nausea, vomiting, and fatigue. Two DLT were observed: dizziness and hypertension. However, the MTD has yet to be established. The PK profile for dose levels up to 90 mg demonstrated rapid absorption and a dose-dependent increase of exposure and Cmax. Disease stabilization for ≥4 cycles has been observed. Conclusions: ZK 304709 was rapidly absorbed and has been tolerated on this schedule at up to 120 mg qd. The MTD has not been reached and enrolment is ongoing. These preliminary data demonstrate that oral delivery on this schedule of an agent that inhibits both cell cycle and angiogenesis is feasible. [Table: see text]

A phase I dose escalation study of pemetrexed in patients with advanced head and neck squamous cell cancer (HNSCC)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 6055-6055 ◽  
Author(s):  
P. H. Morrow ◽  
B. S. Glisson ◽  
L. E. Ginsberg ◽  
S. M. Lippman ◽  
M. S. Kies ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
Cell Cancer ◽  
Maximum Tolerated Dose ◽  
Vitamin Supplementation ◽  
Dose Escalation Study ◽  
Grade 3 ◽  
Ecog Ps ◽  
Dose Levels ◽  
Neck Squamous Cell Cancer

6055 Background: Despite recent advances in therapy, patients (pts) with recurrent or metastatic HNSCC continue to demonstrate a poor median survival. In these pts, early trials with pemetrexed, a novel antimetabolite that acts upon several enzymes involved in pyrimidine and purine synthesis, have demonstrated promising efficacy and tolerability. Prior studies found that the administration of oral dexamethasone with pemetrexed reduced the incidence of skin rash. Later, vitamin supplementation (B12 and folic acid), given in addition to the dexamethasone, further diminished side effects. However, no trial has yet evaluated the appropriate steroid dose and its relation to the dosing of pemetrexed, in the setting of vitamin supplementation. We conducted a phase I trial to determine the maximum tolerated dose, toxicity, and preliminary efficacy of pemetrexed when given with different schedules of, or in the absence of, dexamethasone in pts with advanced HNSCC who had been treated with at least one or more chemotherapy regimens. Methods: Eligible pts had metastatic or recurrent HNSCC, prior treatment with one or more chemotherapy regimens, ECOG PS =2, and life expectancy >3 months. A conventional algorithm-based dose escalation design was applied, with three predefined dose levels (DL) of pemetrexed (500 mg/m2, 600 mg/m2, and 700 mg/m2) within each schedule of dexamethasone (none, 20 mg IV on day 1, and 4 mg orally bid for 3 days). Results: A total of 23 pts have been enrolled; 18 pts were evaluable. Median age was 57 years (range 47–82). Median ECOG PS was 1 (range 0–2), and 75% of pts were male. Number of prior chemotherapy regimens were as follows: 1 (40%), 2 (35%), 3 (15%), and 4 (10%). Preliminary data demonstrated only 2 treatment-related adverse events that were grade 3 or greater: anemia (DL1) and pneumonia (DL 1). In all, 13 pts have received pemetrexed with less than standard recommended dexamethasone dosing (none or IV), including 7 pts who received no dexamethasone. Of the 18 evaluable pts, 1 pt had a partial response and 2 pts had stable disease. Conclusions: This represents the first study that demonstrates that steroids may not be required as premedication with pemetrexed. Due to the limited toxicity observed, trial enrollment continues with dose escalation. [Table: see text]

Phase Ib dose-escalation study of a phase II randomized trial to assess the safety and tolerability of tigatuzumab (CS-1008) in combination with sorafenib in patients (pts) with advanced hepatocellular carcinoma (HCC).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e14617-e14617
Author(s):  
Ann-Lii Cheng ◽  
Yoon-Koo Kang ◽  
Baek-Yeol Ryoo ◽  
Chia-Jui Yen ◽  
Ho Yeong Lim ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Serum Amylase ◽  
Maximum Tolerated Dose ◽  
Clinical Activity ◽  
Advanced Hepatocellular Carcinoma ◽  
Dose Escalation Study ◽  
Phase Ib ◽  
Advanced Hcc ◽  
Rational Combination ◽  
Induced Apoptosis

e14617 Background: Tigatuzumab (T), a humanized monoclonal antibody that acts as a DR5 agonist and exerts tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-like activity, is currently undergoing a phase Ib/II study in advanced HCC. Preclinical studies showed that sorafenib (S) can overcome TRAIL resistance in HCC cells and enhances T-induced apoptosis. In this phase Ib dose-escalation portion of a phase 2 study, safety/tolerability of T + S was evaluated in advanced HCC pts. Methods: Adult pts (≥ 18 years) with advanced HCC and measurable disease (RECIST v1.1), ECOG=0/1, and Child-Pugh A, were administered sequentially-escalating doses of T (2, 4, 6 mg/kg/week IV) in combination with S (400 mg PO BID) over 4 weeks (n = 3/cohort). If no pt had a dose-limiting toxicity (DLT), dose escalation proceeded. If 1/3 pts had DLT, the cohort was to be expanded to 6; if 2/3 or 2/6 pts had DLT, the cohort was to be expanded to 9. Dose escalation was to be stopped when ≥ 3 pts experienced DLTs in a cohort with the prior dose designated as the maximum tolerated dose (MTD). Pts received treatment until disease progression, occurrence of unacceptable toxicity, or withdrawal of consent. Results: Nine pts (3 at each dose level of T + S) were treated in this phase Ib portion. Grade 3/4 treatment-emergent AEs (> 20% incidence) were increased AST, blood amylase, and lipase and hand-foot syndrome. Serious AEs were reported in 5 pts (upper GI hemorrhage, esophageal varices hemorrhage [EVH], tumor progression, increased serum amylase, fever, and lumbar spine compression), which were considered unrelated to study medication except for EVH (T + S), increased serum amylase (T + S), and fever (S). No DLTs were observed and the MTD of T was not reached. 2 pts had a partial response, and 4 pts had disease stabilization. The trial is ongoing. Conclusions: Phase Ib data show that T in combination with S was safely administered with no DLT and demonstrated clinical activity in advanced HCC pts. T and S constitute a promising rational combination treatment for HCC.

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

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 111-111 ◽  
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.

First-in-human (FIH) phase I study of GST-HG161, a potent and highly selective c-met inhibitor, in patients with advanced solid tumor.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e16126-e16126
Author(s):  
Jin Li ◽  
Ye Guo ◽  
Junli Xue ◽  
Wenqiang Wu ◽  
Shikui Chen ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Maximum Tolerated Dose ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Dose Escalation Study ◽  
Dose Cohort ◽  
Patient Reported ◽  
Met Inhibitor ◽  
Dose Levels

e16126 Background: GST-HG161 is an orally bioavailable novel potent and highly selective c-Met inhibitor, which displayed significant antitumor activity in preclinical models as well as very desirable pharmaceutical properties for oral dosing. Preclinical studies demonstrated that GST-HG161 has the potential to be effective in HCC patients with active c-Met signaling. Methods: This is an open label, first-in-human, single center, dose-escalation study (NCT04228406) utilizing an accelerated dose escalation design using single patient cohorts for the first two dose levels (60 and 150 mg) followed by a conventional 3+3 design at the 3rd dose cohort (300 mg). Dose escalation is expected to continue to the proposed 7th dose cohort (900 mg). The objective of the study is to determine the maximum tolerated dose and/or recommended Phase II dose, dose limiting toxicities (DLT), safety, pharmacokinetics, pharmacodynamics and preliminary signals of anticancer efficacy of GST-HG161 in patients with advanced solid tumors. Eligible patients are adults with advanced solid tumors refractory to standard therapies with confirmed c-Met positive. The definition of c-Met positive is a) IHC expression of c-Met (positive criteria: 1+ and above) and/or b) FISH amplification of c-Met and/or c) MET exon 14 (METex14) skipping. GST-HG161 is administered orally once-a-day starting on day 1 of each 21 days cycle. Results: To date, 6 patients (CRC 2, Gastric 1, NSCLC 1, HCC 1, Cholangiocarcinoma 1) were enrolled to 3 dose levels (60, 150, and 300 mg). Of these 6 patients, 4 had discontinued GST-HG161 treatment at the data cut-off date of Feb 1, 2020, due to progressive disease (3) and adverse event (1). Two patients at the 300 mg cohort are still on treatment. Overall, 4/6 patients showed no drug-related AEs > Grade 1. One patient reported a DLT: asymptomatic Grade 3 lipase elevation after a single dose of 60mg. To date, no other patients showed elevations of lipase and amylase. Bioanalysis of PK samples from study patients are currently ongoing. PK summary will be reported in the presentation. Conclusions: GST-HG161 has been well tolerated to date in study patients with a manageable safety profile. The dose escalation is expected to continue to the proposed 7th cohort at 900 mg. Clinical trial information: NCT04228406 .

scholarly journals A phase Ib, open label, dose escalation trial of the anti-CD37 monoclonal antibody, BI 836826, in combination with ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia

2021 ◽  
Author(s):  
Alexey V. Danilov ◽  
Stephen E. Spurgeon ◽  
Tanya Siddiqi ◽  
Anne-Marie Quinson ◽  
Daniela Maier ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Dose Escalation ◽  
Residual Disease ◽  
Transmembrane Protein ◽  
Complete Response ◽  
Maximum Tolerated Dose ◽  
Lymphocytic Leukemia ◽  
Open Label ◽  
Dose Escalation Study ◽  
Phase Ib

SummaryBI 836826 is a chimeric immunoglobulin G1 antibody targeting CD37, a transmembrane protein expressed on normal and malignant B cells. This open-label, phase Ib, dose-escalation study was conducted to determine the recommended phase II dose (RP2D) of BI 836826 + ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia (CLL). Eligible patients received 420 mg/day of ibrutinib with escalating doses of BI 836826. BI 836826 was administered in 4-week cycles. After Cycle 12, patients achieving complete response (CR), CR with incomplete marrow recovery, or minimal residual disease-negative partial response could continue to receive BI 836826 + ibrutinib every 4 weeks for ≤ 12 additional cycles. Patients received either 100 mg (n = 3) or 200 mg (n = 3) BI 836826 + ibrutinib. In the 100 mg BI 836826 cohort, one patient received two cycles and two patients received 22 cycles of BI 836826. In the 200 mg BI 836826 cohort, patients received 12, 16 and 20 cycles of BI 836826, respectively. All patients discontinued BI 836826 and continued ibrutinib outside the trial. No dose-limiting toxicities were reported in the maximum tolerated dose (MTD) evaluation period. As the trial was discontinued before the MTD was reached, the RP2D was not determined. Grade 3/4 adverse events (AEs) were predominantly hematological. Pseudomonal bacteremia was the only drug-related AE of special interest. BI 836826 + ibrutinib did not exceed the MTD at doses up to 200 mg in patients with CLL. However, RP2D and MTD were not formally established, as the sponsor discontinued the trial.

Preliminary activity in adrenocortical tumor (ACC) in phase I dose escalation study of intermittent oral dosing of OSI-906, a small-molecule insulin-like growth factor-1 receptor (IGF-1R) tyrosine kinase inhibitor in patients with advanced solid tumors

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 3544-3544 ◽  
Author(s):  
C. P. Carden ◽  
S. Frentzas ◽  
M. Langham ◽  
I. Casamayor ◽  
A. W. Stephens ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Small Molecule ◽  
Dose Escalation ◽  
Kinase Inhibitor ◽  
Lung Metastases ◽  
Maximum Tolerated Dose ◽  
Dose Escalation Study ◽  
Heavily Pretreated ◽  
Plasma Insulin Levels ◽  
Dose Levels

3544 Background: IGF-1R is overexpressed in various malignancies, and implicated in proliferation, survival, and metastasis. IGF-1R blockade increases apoptosis and reduces tumor growth in preclinical models. OSI-906 is an oral small molecule tyrosine kinase IGR-1R inhibitor. Methods: Patients (pt) with advanced solid tumours were enrolled to determine safety, tolerability, maximum tolerated dose, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary anti-tumor activity. Results: 26 pt have been treated (14M:12F, median age 61 yrs) at 10, 20, 40, 80, 150, 300, and 450 mg on days (d) 1–3 q14 d. No dose-limiting toxicities have been observed to date. Drug-related toxicities include grade 1 fatigue, nausea, rash, diarrhea, tachycardia, proteinuria, pruritis and peripheral oedema. Linear PK was observed, with median terminal t1/2 3.5 hr; AUC0-∞ 25.8 μg.hr/mL; Cmax 3.20 μg/ml at 450mg. Plasma OSI-906 concentrations above the estimated efficacious concentration (1 μM) were attained at doses > 40mg. Glucose did not increase with rising OSI-906 concentration, but plasma insulin levels showed an upward trend, indicating potential PD effects. PD data on IGFR phosphorylation were analyzed. In total, 11 pt were treated for > 12 weeks (w). Of 3 pt with ACC, 1 pt had a partial response (43% reduction in primary and multiple lung metastases) and remains on treatment after 16 w, 1 pt was treated for 32 w, and 1 pt progressed after 4 w at 40mg. In addition, 1 pt with heavily pretreated NSCLC was treated for 43 w and 1 pt with progressive myxoid chondrosarcoma remains on treatment after 38 w. Conclusions: OSI 906 had minimal toxicity, dose proportional PK at dose levels up to 450mg tested d 1–3 q14 d, with preliminary antitumor activity seen, particularly in ACC. Dose escalation with 5 and 7 d schedules q14 d continues. [Table: see text]

A phase IB study of CX-4945 in combination with gemcitabine plus cisplatin in the frontline systemic treatment of patients with advanced cholangiocarcinoma.

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 294-294 ◽  
Author(s):  
Mitesh J. Borad ◽  
Joleen Marie Hubbard ◽  
Do-Youn Oh ◽  
Sun Young Rha ◽  
Kabir Mody ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Toxicity Assessment ◽  
Model Systems ◽  
Toxicity Profile ◽  
Phase 2 ◽  
Efficacy Evaluation ◽  
Dose Escalation Study ◽  
Phase Ib

294 Background: CX-4945 is a first-in-class casein kinase-2 (CK2) threonine kinase small molecule inhibitor. CK2 is pleiotropic and regulates key cellular processes such as proliferation and DNA damage repair, and has been shown to enhance efficacy of gemcitabine (G) and cisplatin (C) in cell line and xenograft CCA model systems. A Phase IB study of G+C with CX-4945 was conducted in advanced cholangiocarcinoma (CCA) patients. Methods: A multi-center “3+3” dose escalation study was conducted in advanced CCA patients. Eligible patients had ECOG PS 0-1 and adequate hematologic, hepatic, and renal function. Primary endpoints were maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D). Secondary endpoints included pharmacokinetic (PK) analyses, overall toxicity evaluation and preliminary assessment of efficacy. Routine clinical dosing for G (1000 mg/m2) and C (25 mg/m2), both on days 1 and 8 every 21 days, was used. Dose escalation cohort were CX-4945 given twice daily on days 0,1,2 and 7,8,9 at 200 mg (DL1), 400mg (DL2), 600 mg (DL3), 800 mg (DL4) and 1000 (DL5) mg. NCI CTCAE v4.03 was used for toxicity assessment and RECIST v1.1 for efficacy evaluation. Results: Nineteen patients were enrolled (DL1:n = 3; DL2:n = 4 DL3:n = 3; DL4:n = 4; DL5:n = 5). No dose limiting toxicities were encountered. MTD and RP2D were ascertained to be DL5. No grade 3 or 4 toxicities at prevalence > 10% were encountered and the overall toxicity profile of the combination was reflective of standard G+C toxicity profile. At data cut-off, preliminary efficacy evaluation demonstrated disease control rate (CR+PR+SD) of 64% (PR:32%, SD:32% and CR:0%), along with median progression-free survival (PFS) of 5 months (range 0-14 months). PK analyses showed no evidence of drug-drug interactions between G, C and CX-4945. Conclusions: RP2D for G+C with CX-4945 is DL5 (CX-4945 dosed on days 0,1,2 and 7,8,9 at 1000 mg PO bid with standard G and C dosing). Preliminary clinical efficacy and tolerability of the regimen support planned controlled, randomized Phase 2 evaluation. Clinical trial information: NCT02128282.

scholarly journals Phase I Dose-Escalation Study of Docetaxel, Cisplatin, and 5-Fluorouracil Combination Chemotherapy in Patients With Advanced Esophageal Carcinoma

2015 ◽  
Vol 100 (6) ◽  
pp. 1153-1158 ◽  
Author(s):  
Hitoshi Satomura ◽  
Masanobu Nakajima ◽  
Kinro Sasaki ◽  
Satoru Yamaguchi ◽  
Yasushi Domeki ◽  
...  
Keyword(s):  
Esophageal Carcinoma ◽  
Combination Chemotherapy ◽  
Dose Escalation ◽  
Maximum Tolerated Dose ◽  
Combination Regimen ◽  
Dose Escalation Study ◽  
Highly Active ◽  
Level 3 ◽  
Dose Levels ◽  
Level 2

A dose-escalation study of docetaxel (DOC), cisplatin (CDDP), and 5-fluorouracil (5-FU; DCF combination regimen) was performed to determine the maximum-tolerated dose (MTD), recommended dose (RD) and dose-limiting toxicities (DLT) in advanced esophageal carcinoma. Eighteen patients with esophageal carcinoma were enrolled and received DCF combination therapy at different dose levels. DLTs included febrile neutropenia and oral mucositis. DLT occurred in 2 out of 6 patients at level 2 and 3. The study proceeded to level 4, according to the protocol. The level 4 dose was defined as the MTD and the level 3 dose was defined as the RD. The RD for DCF combination chemotherapy for advanced esophageal carcinoma in the present study was 70 mg/m2 DOC plus 70 mg/m2 CDDP on day 1 plus 700 mg/m2 5-FU on days 1–5 at 4-week intervals. This regimen was tolerable and highly active. A phase II study has been started.

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