A phase IB study of the combination of selumetinib (AZD6244; ARRY-142886) and cyclosporin A (CsA) in patients with advanced solid tumors with an expansion cohort in metastatic colorectal cancer (mCRC).

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 609-609 ◽  
Author(s):  
Anuradha Krishnamurthy ◽  
A. Dasari ◽  
Albert C. Lockhart ◽  
Mark N. Stein ◽  
Hanna Kelly Sanoff ◽  
...  
Keyword(s):  
Phase I ◽  
Cyclosporin A ◽  
Solid Tumors ◽  
Dose Level ◽  
Dose Escalation ◽  
Wnt Pathway ◽  
Response To Therapy ◽  
Advanced Solid Tumors ◽  
Grade 3 ◽  
Expansion Cohort

609 Background: Targeting MEK is of interest in the development of novel agents for treatment of many malignancies. However, better strategies are needed to overcome acquired resistance to MEK inhibitors. Preclinical studies have shown Wnt pathway overexpression in KRAS mutant cell lines resistant to the MEK inhibitor, Selumetinib. The combination of selumetinib and cyclosporin A (CsA), a non-canonical WnT pathway modulator, demonstrated antitumor activity in patient-derived xenograft (PDX) models. We are conducting an NCI CTEP-approved Phase I/IB trial (NCI # 9571/COMIRB # 13-2628) of selumetinib and CsA combination. Biomarkers of response to therapy are being co-developed. We hypothesize that this combination will be safe and potentially effective in patients with mCRC and that upregulation of FZD2 may predict for sensitivity. Methods: Phase I trial with initial dose escalation investigating the combination of selumetinib and CsA in patients with advanced solid tumors (n = 18) followed by an expansion cohort in patients with irinotecan and oxaliplatin-refractory mCRC (n = 20). The expansion cohort utilizes a selumetinib “run-in” to evaluate efficacy in RAS-WT and RAS-MT mCRC to identify those patients most likely to respond to the combination. Results: 18 patients were enrolled in the dose escalation phase and 10 patients have been enrolled in the dose expansion phase as of September 2016. Grade 1 or 2 nausea and rash were reported as the most common AEs. Most commonly reported Grade 3 or 4 toxicities were hypertension, elevated liver enzymes and rash. Three DLTs were reported with Grade 3 hypertension noted at dose level 1 and 2 and grade 3 rash reported at dose level 2. The maximum tolerated dose was defined as Selumetinib 75 mg BID and CsA 2 mg/kg BID on a 28-day cycle. Two partial responses and sixteen stable disease responses have been observed. Six patients have exhibited progressive disease. Conclusions: Selumetinib in combination with cyclosporin A appears to be well-tolerated with evidence of activity in solid tumors. Expansion cohort will complete enrollment this month. Clinical trial information: NCT02188264.

A phase IB study of the combination of selumetinib (AZD6244, ARRY-142886) and cyclosporin A (CsA) in patients with advanced solid tumors with an expansion cohort in metastatic colorectal cancer (mCRC).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 2587-2587 ◽  
Author(s):  
Anuradha Krishnamurthy ◽  
A. Dasari ◽  
Anne M. Noonan ◽  
Janice M. Mehnert ◽  
Albert C. Lockhart ◽  
...  
Keyword(s):  
Cyclosporin A ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Wnt Pathway ◽  
Response To Therapy ◽  
Cancer Drug ◽  
Advanced Solid Tumors ◽  
Potential Biomarker ◽  
Grade 3 ◽  
Expansion Cohort

2587 Background: MEK inhibition is of interest in cancer drug development. However, better strategies are needed to overcome acquired resistance to MEK inhibitors. Preclinical studies have shown Wnt pathway overexpression in KRAS mutant cell lines resistant to the MEK inhibitor, selumetinib. The combination of selumetinib and cyclosporin A (CsA), a non-canonical Wnt pathway modulator, demonstrated antitumor activity in patient-derived xenograft (PDX) models. We conducted an NCI CTEP-approved Phase I/IB trial (NCI # 9571/COMIRB # 13-2628/NCT02188264) of selumetinib and CsA combination. Biomarkers of response are being co-developed. Methods: Patients with advanced solid tumors were treated with the combination of selumetinib and CsA in dose escalation followed by an expansion cohort in patients with irinotecan and oxaliplatin-refractory mCRC (n = 20). The expansion cohort utilized a selumetinib “run-in” to evaluate efficacy in RAS-WT and RAS-MT mCRC to identify those patients most likely to respond to the combination. Results: As of January 2017, 18 patients were enrolled in the dose escalation phase and 20 patients were enrolled in the dose expansion phase. The most common adverse events and grade 3/4 toxicities were rash, hypertension, and edema. Three DLTs - Grade 3 hypertension, rash and increased creatinine were reported. The maximum tolerated dose was identified as selumetinib 75 mg BID and CsA 2 mg/kg BID on a 28-day cycle. The selumetinib “run-in” did not favor a specific RAS type. Two partial responses were noted. Sixteen patients had stable disease, and 6 patients had progression of disease as their best response to therapy. Conclusions: Selumetinib in combination with cyclosporin A appears to be well tolerated with evidence of activity in mCRC. Tumor response data are currently being updated. FZD will be evaluated as a potential biomarker of response. Clinical trial information: NCT02188264.

Phase I study of topotecan and cisplatin in patients with advanced solid tumors: a cancer and leukemia group B study.

1994 ◽  
Vol 12 (12) ◽  
pp. 2743-2750 ◽  
Author(s):  
A A Miller ◽  
J B Hargis ◽  
R C Lilenbaum ◽  
S Z Fields ◽  
G L Rosner ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Level ◽  
Phase Ii ◽  
Dose Escalation ◽  
Topoisomerase I ◽  
Advanced Solid Tumors ◽  
Phase Ii Trials ◽  
Grade 3 ◽  
Dose Levels

PURPOSE The objectives of this phase I trial were to determine the dose-limiting toxicities (DLTs) of the novel topoisomerase I inhibitor topotecan combined with cisplatin, to define the maximum-tolerated doses (MTDs) of the combination without and with the use of filgrastim, and to define recommended doses for phase II trials. PATIENTS AND METHODS Patients with advanced solid tumors were eligible if they had normal bone marrow, renal, and hepatic function and had not previously been treated with platinum compounds. Topotecan was administered intravenously on days 1 through 5 and cisplatin was administered intravenously on day 1 of a 21-day cycle. The topotecan dose was fixed at 1.0 mg/m2/d on the first four dose levels, and cisplatin was escalated in 25-mg/m2 increments from 25 to 100 mg/m2 without filgrastim. After encountering DLT, the dose of cisplatin was decreased by one level and topotecan dose escalation was attempted. After defining the MTD without growth factor, the study proceeded with escalating cisplatin doses to define the MTD with filgrastim 5 micrograms/kg subcutaneously (SC) daily starting on day 6 of treatment. Priming with filgrastim 5 micrograms/kg SC on days -6 to -2 before the first course was explored last. RESULTS Of 38 patients entered, 37 were eligible, 35 assessable for toxicity in the first course, and 28 assessable for response. The principal toxicity was grade 4 neutropenia, which had to last more than 7 days to be considered dose-limiting. No DLT was observed at the starting cisplatin dose of 25 mg/m2 (dose level 1). On level 2 (cisplatin 50 mg/m2, one patient had dose-limiting neutropenia and one patient had grade 3 renal toxicity. On level 3 (cisplatin 75 mg/m2), two patients had dose-limiting neutropenia. Therefore, cisplatin dose escalation was stopped. On dose level 5 (cisplatin 50 mg/m2 and topotecan 1.25 mg/m2/d), one patient had grade 4 neutropenia that lasted more than 7 days and one patient died of neutropenic sepsis. The remaining dose levels used topotecan 1.0 mg/m2/d plus cisplatin 75 mg/m2 (level 6) and 100 mg/m2 (levels 7 and 8) with filgrastim. No DLT was observed on level 6. On level 7, two patients had dose-limiting neutropenia and one patient had grade 3 hyperbilirubinemia. Priming with filgrastim on level 8 demonstrated no obvious advantage over level 7, and one patient had grade 4 thrombocytopenia that lasted more than 7 days. Three patients with non-small-cell lung cancer achieved a partial response and one patient with breast cancer had a complete response. CONCLUSION Topotecan and cisplatin in combination cause more neutropenia than expected from either drug given alone at the same dosage. The recommended phase II doses are topotecan 1.0 mg/m2/d for 5 days in combination with cisplatin 50 mg/m2 on day 1 without filgrastim or cisplatin 75 mg/m2 on day 1 with filgrastim support.

Phase I study of the HSP90 inhibitor AUY922 in combination with capecitabine as treatment for patients with advanced solid tumors.

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 475-475
Author(s):  
Johanna C. Bendell ◽  
Lowell L. Hart ◽  
Shubham Pant ◽  
Jeffrey R. Infante ◽  
Suzanne Fields Jones ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Level ◽  
Phase I Study ◽  
Standard Dose ◽  
Heat Shock Protein 90 ◽  
Competitive Inhibitor ◽  
Maximum Tolerated Dose ◽  
Advanced Solid Tumors ◽  
Grade 3

475 Background: Heat shock protein 90 (HSP90) is a molecular chaperone involved in the maintenance and function of client proteins, many of which are integral to key oncogenic processes. AUY922 is a competitive inhibitor of HSP90, with demonstrated activity in a variety of preclinical models. Further preclinical evidence suggests potential synergy between inhibition of HSP90 and fluorouracil treatment (Burkitt et al. 2007). This phase I study was designed to determine the maximum tolerated dose (MTD) of AUY922 in combination with standard dose of capecitabine as treatment for patients with advanced solid tumors. Methods: Patients with refractory solid tumors for which capecitabine was an appropriate therapy received AUY922 with capecitabine in a standard 3+3 dose escalation. Capecitabine 1000mg/m2 was administered twice daily for days 1-14 of 21-day cycles, with escalating doses of AUY922 administered by intravenous (IV) infusion on days 1, 8, and 15; the 6th dose level combined the MTD of AUY922 with capecitabine 1250mg/m2. Dose-limiting toxicities (DLTs), safety, and efficacy were evaluated. Results: 23 patients were treated at 6 dose levels: 22mg/m2 (n = 3); 28mg/m2 (n = 3); 40mg/m2 (n = 3); 55mg/m2 (n = 5); 70mg/m2 (n = 3); 70mg/m2 with capecitabine 1250mg/m2 (n = 6). There were no DLTs observed until the 6th dose level (grade 3 diarrhea). Common adverse events (all grades) included: diarrhea (61%), nausea (57%), fatigue (43%), hand-foot skin reaction (39%), anorexia (39%), vomiting (35%), rash (30%), and darkening vision (22%). Myelosuppression was uncommon, with no instances of grade ≥3 thrombocytopenia, and only 2 patients (9%) with grade 3/4 neutropenia (1 patient each). Of the 19 patients evaluable for response per RECIST 1.1, unconfirmed partial response (PR) was noted in 3 patients (13%; colorectal, 1; breast, 1; stomach, 1), with 1 additional confirmed PR (4%; colorectal); two of these had progressed on prior fluorouracil. Stable disease was noted in 8 patients (35%). Conclusions: The addition of AUY922 to standard dose capecitabine was well-tolerated at doses of up to 70mg/m2. Preliminary efficacy is encouraging, and warrants further investigation of this regimen. Clinical trial information: NCT01226732.

Pooled analysis of phase I dose-escalation and dose cohort expansion studies of IMP4297, a novel PARP inhibitor, in Chinese and Australian patients with advanced solid tumors.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 3059-3059 ◽  
Author(s):  
Junning Cao ◽  
Pin Zhang ◽  
Paul L. de Souza ◽  
Bo Gao ◽  
Mark Voskoboynik ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Level ◽  
Dose Escalation ◽  
Single Agent ◽  
Response To Treatment ◽  
Clinical Activity ◽  
Dose Cohort ◽  
Phase Ii Studies ◽  
Grade 3

3059 Background: Poly (ADP-ribose) polymerase (PARP) enzymes play critical roles in DNA damage detection and repair. IMP4297 is a novel, potent PARP1/2 inhibitor (IC50 6.27nM/1.57nM) and has demonstrated to be 20-fold more potent than Olaparib in anticancer animal models. Two phase I studies were performed to evaluate and characterize the tolerability and safety, pharmacokinetics, and antitumor activity of single agent IMP4297 in Chinese and Australian patients with advanced ovarian, breast, prostate and other solid tumors. Methods: Dose escalation used a 3+3 design with a modified Fibonacci escalation. Dose cohort expansion was planned after efficacy was observed at the lowest dose level. Patients received IMP4297 monotherapy orally once a day until disease progression or unacceptable toxicity. Results: As of Jan 12, 2019, 56 patients, including 23 BRCA mutation carriers (BRCA+), had been enrolled at 2-100 mg dose level. No DLT was observed. In these two studies, the most frequent treatment-related adverse events (TRAEs) were leukopenia (20%), followed by anemia (18%), nausea (18%) and thrombocytopenia (14%). The majority of TRAEs were grade 1 or 2. Grade 3 TRAEs occurred in five patients (anemia, n=2; vomiting, n=1; thrombocytopenia, n=1; elevated AST, n=1). Only one patient had a dose reduction due to grade 3 thrombocytopenia. No serious TRAEs were observed. In 15 BRCA+ patients who had measurable lesions, the ORR was 33% and the DCR was 80%. There were 4 BRCA+, platinum-sensitive ovarian cancer patients with an ORR of 75% and a DCR of 100%. One patient with somatic BRCA mutated urothelial carcinoma showed a 76% decrease in tumor size. Conclusions: IMP4297 has been well-tolerated with significant anti-tumor activity. The 100 mg daily dose was selected as the RP2D based on safety, pharmacokinetics and clinical activity, and will be further characterized in dose expansion and phase II studies. Tumor response to treatment (RECIST 1.1) in patients with measurable lesions. Clinical trial information: NCT03508011 and NCT03507543. [Table: see text]

Dose escalation and expansion cohort study for DS-8895a in patients with advanced solid tumors.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 99-99 ◽  
Author(s):  
Taroh Satoh ◽  
Kohei Shitara ◽  
Satoru Iwasa ◽  
Kensei Yamaguchi ◽  
Kei Muro ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Stable Disease ◽  
Japanese Patients ◽  
Maximum Tolerated Dose ◽  
Advanced Solid Tumors ◽  
Igg1 Monoclonal Antibody ◽  
Grade 3 ◽  
Expansion Cohort

99 Background: Erythropoietin-producing hepatocellular receptor A2 (EPHA2) is overexpressed on the cell surface of many tumors and is associated with poor prognosis, suggesting EPHA2 as a target for cancer therapy. DS-8895a is an afucosylated, humanized anti-EPHA2 IgG1 monoclonal antibody with potent cytotoxicity. We report results from a phase I clinical trial to determine safety, tolerability, and pharmacokinetics (PK) of DS-8895a in Japanese patients with advanced solid tumors (NCT02004717). Methods: Step 1 (dose escalation cohort) had patients with advanced solid tumors and comprised of six dose levels (0.1–20 mg/mL, intravenous infusion, every 2 weeks [Q2W]) with a 28-day dose limiting toxicity (DLT) evaluation period. Step 2 (expansion cohort) patients had gastric or esophageal cancer confirmed to be EPHA2 positive by immunohistochemistry. Dose level in Step 2 was determined based on results obtained in Step 1. We evaluated safety, PK, potential biomarkers including circulating NK cells and cytokines, and tumor response. Results: Maximum tolerated dose was not reached in Step 1 (n = 22). DS-8895a was administered at 20 mg/kg Q2W in Step 2 (n = 15). Among 37 patients in the safety analysis set, adverse events (AEs) were reported in 97.3% (64.9% drug-related); 35.1% presented grade ≥ 3 AEs (8.1% drug-related). Dose delay and study discontinuation due to AEs (treatment related: grade 4 platelet decrease, hypoesthesia, hypotension, peripheral coldness, nausea, and vomiting) were observed in one and four patients (20 mg/kg), respectively. Infusion-related reactions occurred in 51.4% of patients resulting in 10 dose interruptions with one discontinuation. Serum inflammatory cytokines were transiently increased 4 h from the end of infusion drug administration. Serum DS-8895a maximum and trough concentrations increased dose-dependently. Biomarkers had no apparent relationship to best overall response. Seven patients in Step 1 achieved stable disease; in Step 2, six patients achieved stable disease and one patient achieved partial response. Conclusions: DS-8895a was safe and well tolerated up to 20 mg/kg. The PK of DS-8895a was dose-dependent as expected. Clinical trial information: NCT02004717.

Phase I trial of combination becatecarin and oxaliplatin in patients with advanced solid tumors

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 2561-2561
Author(s):  
S. Manda ◽  
C. Mauser ◽  
J. Bokar ◽  
M. Cooney ◽  
J. Brell ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Level ◽  
Phase Ii ◽  
Phase I Trial ◽  
Performance Status ◽  
Advanced Solid Tumors ◽  
Phase Ii Studies ◽  
Grade 3 ◽  
Level 2

2561 Background: Becatecarin (rebeccamycin analogue-RA) is an anti-tumor antibiotic with inhibitory activity against both topoisomerase II and I as well as DNA intercalating properties. We performed a phase I trial to a) determine the maximum tolerated dose (MTD) of RA in combination with oxaliplatin; b) determine the dose limiting toxicities (DLT) (c) obtain data on pharmacokinetics and (d) observe for any antitumor activity. Methods: Eligibility criteria included patients with advanced solid tumors refractory to standard therapy; performance status 0–2; adequate hematologic, renal and liver function. Patients were treated with RA as a 1 hour infusion daily x 5 and oxaliplatin on day 5 only, after RA infusion. Treatment was repeated q 21 days. The following dose levels were evaluated: Dose level 1: RA 80 mg/m2/d and oxaliplatin 90 mg/m2; Dose level 2: RA 80 mg/m2/d and oxaliplatin 130 mg/m2; Dose level 3: RA 110 mg/m2/d and oxaliplatin 130 mg/m2. Results: A total of 15 evaluable patients were enrolled. Median age was 56 (8 male, 7 female). A variety of tumor types were enrolled. A total of 56 cycles were administered. DLT occurred at a dose of RA at 110 mg/m2/d x 5 days and oxaliplatin at 130 mg/m2 and consisted of grade 3 hypophosphatemia and grade 4 atrial fibrillation. At this dose level 2 of 3 enrolled patients also developed grade 3 neutropenia. The MTD and recommended phase II dose was RA at 80 mg/m2/daily x 5 along with oxaliplatin 130 mg/m2 day 5 q 21 days. Three confirmed partial responses were observed in patients with hepatocellular, gallbladder and esophageal cancers. Six patients experienced stable disease. Conclusions: At the MTD combination RA and oxaliplatin is well tolerated and given the response rate and stable diseases observed, phase II studies are recommended. Supported by Grants U01 CA62502, MO1-RR-00080, K23 CA109348–01 from the National Institutes of Health. No significant financial relationships to disclose.

A phase I study of vorinostat (VOR) in combination with capecitabine (CAP) in patients (pts) with advanced solid tumors

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3576-3576 ◽  
Author(s):  
P. Tang ◽  
A. Oza ◽  
C. Townsley ◽  
L. Siu ◽  
G. Pond ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Level ◽  
Phase I Study ◽  
Zinc Ion ◽  
Advanced Solid Tumors ◽  
Prior Therapy ◽  
Disease Stabilization ◽  
Grade 3 ◽  
Tumor Types

3576 Background: VOR (suberoylanilide hydroxamic acid; SAHA) is a small molecule inhibitor of histone deacetylase (HDAC) that binds directly to the enzyme’s active site in the presence of a zinc ion. Aberrant HDAC activity has been implicated in a variety of cancers. The combination of 5-fluorouracil and VOR is synergistic in preclinical tumor models. Methods: This phase I study evaluated safety, tolerability, and the recommended phase II dose (RPTD) of VOR and CAP in pts with advanced solid tumors. VOR was administered orally daily while CAP was administered orally bid on days 1–14 of a 21 d cycle. Results: Three dose levels have been evaluated (VOR (mg/d)/CAP (mg/bid)): 300/750, 300/1,000 and 400/1,000. Twenty-three pts have been treated: 6M/17F, median age 59 (range 41–73), ECOG 0:1:2 = 9:13:1, prior therapy 1:2:3 or more = 3:7:13. Pts had colorectal cancer (n=6), nasopharyngeal (n=3) and various other tumors. A total of 104 cycles have been administered, with median = 2 (range 1–15). One dose limiting toxicity (DLT) (grade 3 diarrhea) occurred in 6 patients at dose level 1. No DLT were observed at dose level 2, and 2 DLTs (grade 3 fatigue and grade 3 nausea/vomiting) occurred at dose level 3. RPTD was determined to be VOR 300 mg/d and CAP 1,000 mg/bid. Most common toxicities of any grade and at least possibly attributable (n=22) are: thrombocytopenia (59% of pts), fatigue (55%), nausea (55%), vomiting (50%), hypoalbuminemia (45%), anemia (41%), diarrhea (41%), anorexia (41%), elevated creatinine (36%), lymphopenia (36%), hyponatremia (36%), and hyperglycemia (36%). Common grade 3 toxicities included: hand-foot syndrome (23% of pts), diarrhea (14%), fatigue (14%), and lymphopenia (14%). One pt died on study from ventricular fibrillation due to sotalol and hypocalcemia from pre-existing hypoparathyroidism. Five patients with various tumor types had PR (2 confirmed, 3 unconfirmed) (2 nasopharyngeal, 1 each of ovarian, endometrial and squamous cell carcinoma of head and neck). In addition, disease stabilization was seen in 12 patients. Conclusions: VOR and CAP are well tolerated, and this combination is active in several tumor types. Further evaluations of VOR and CAP are warranted. No significant financial relationships to disclose.

Dual epidermal growth factor receptor (EGFR) inhibition: Phase I study combining cetuximab (C225) and erlotinib (E) in advanced solid tumors

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 3552-3552
Author(s):  
R. Sangha ◽  
C. Ho ◽  
L. Beckett ◽  
D. H. Lau ◽  
P. N. Lara ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Level ◽  
Phase Ii ◽  
Dose Escalation ◽  
Gene Copy ◽  
Hematologic Toxicity ◽  
Advanced Solid Tumors ◽  
Egfr Inhibition ◽  
Biomarker Analysis

3552 Background: The EGFR pathway is implicated in lung tumorigenesis by aberrantly regulating cell proliferation, apoptosis, and invasion. Maximal blockade of the EGFR can be achieved by dually inhibiting the extracellular and intracellular domain with the monoclonal antibody C225 and the tyrosine kinase inhibitor, E. Given preclinical synergy of C225 and E, we hypothesized this combination would be feasible and result in improved therapeutic benefit. Methods: Patients (pts) with advanced solid tumors were enrolled using a standard phase I dose escalation design. C225 was administered IV weekly, with no loading dose, and E given orally daily on a 28-day cycle. Four dose levels were studied: C225 150 mg/m2, E 100 mg; C225 200 mg/m2, E 100 mg; C225 250 mg/m2, E 100 mg; and C225 250 mg/m2, E 150 mg. Dose limiting toxicity (DLT) was defined as: grade (Gr) 4 platelets, Gr 3 platelets with bleeding, febrile neutropenia, ≥ Gr 3 ANC with documented infection, or clinically significant > Gr 3 non-hematologic toxicity. Gr 3 rash based solely on pain or Gr 3 hypersensitivity infusion reactions were not considered DLTs. Results: 18 pts were treated: 13 NSCLC, 3 H&N, 1 pancreas, and 1 invasive thymoma. Characteristics: Age range 41–80, median 62.5; Gender: 7 M; ECOG PS ≤1 = 17; Prior chemo ≤1 = 10. Planned dose escalation was completed without reaching the MTD. The highest dose level was expanded to 6 pts. A single DLT for Gr 3 diarrhea was observed at the second dose level (C225 200 mg/m2, E 100 mg). Gr 3/4 toxicities were: lymphopenia (3), acneiform rash (3), nausea/vomiting (3), pruritis (1), fatigue (1), diarrhea (1), confusion (1), hypomagnesemia (1), hypocalcemia (1), hyponatremia (1), hyperkalemia (1), and anemia (1). Of 13 evaluable pts, 1 PR (NSCLC) and 4 with SD (2 NSCLC, 2 H&N). Median cycles: 2 (1–14) with one NSCLC pt on therapy for 8 cycles and one H&N pt receiving 14 cycles. Biomarker analysis of EGFR polymorphisms, gene copy number via FISH, and protein expression will be presented, along with the mutation status of EGFR and KRAS. Conclusions: 1) Dual EGFR inhibition with C225 250 mg/m2 weekly and E 150 mg daily is feasible, well tolerated, and the recommended phase II dose. 2) Efficacy of this combination in NSCLC is being evaluated in a phase II trial. [Table: see text]

A first-in-human phase I study of oral pan-CDK inhibitor BAY 1000394 in patients with advanced solid tumors: Dose escalation with an intermittent 3 days on/4 days off schedule.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3012-3012 ◽  
Author(s):  
Rastislav Bahleda ◽  
Anas Gazzah ◽  
Andrea Varga ◽  
Prabhu Rajagopalan ◽  
David Andrew Henderson ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Oral Solution ◽  
Tablet Formulation ◽  
Nausea And Vomiting ◽  
Cdk Inhibitor ◽  
Advanced Solid Tumors ◽  
Antiemetic Treatment ◽  
Grade 3

3012 Background: BAY 1000394 (BAY) is an oral pan-CDK inhibitor targeting CDKs 1,2,4, 7 and 9 in the low nanomolar range. A phase I dose escalation study was initiated to determine the maximum tolerated dose (MTD), pharmacokinetics (PK), and pharmacodynamics (PD) in patients (pts) with advanced solid tumors. Methods: BAY was administered twice daily in a 3 days on / 4 days off schedule (cycle length 21 days, 3+3 design). PK was evaluated on cycle 1 day 1 and day 10. Response rate was assessed according to RECIST 1.1. PD markers included CK18 fragments in plasma. Results: As of Jan 08 2011, 34 pts were treated at doses of 0.6 (3 pts), 1.2 (4), 2.4 (3), 4.8 (3), 9.6 (3), 19.2 (6) mg per day as oral solution and at doses of 10 (4), 15 (6) and 20 (2) mg per day as tablet. Tumor types included 10 colorectal, 4 mesothelioma and 20 others. Cohort 9 (20 mg tablet) is ongoing. Frequent CTCAEv4 grade 1/2 drug related AEs occurring in more than 25% of patients up to cohort 8 were asthenia, diarrhea, nausea, vomiting and anorexia. DLTs (grade 3, 1 pt each) were hyponatremia, aphtous stomatitis at 19.2 mg solution and arterial thrombosis at 15 mg tablet. Aphthous stomatitis (20%) has not been observed with the tablet formulation. Other grade 3 related AEs were asthenia in 2 and nausea and vomiting in one pt each. Nausea and vomiting on treatment days were observed despite antiemetic treatment (aprepitant +/- setron). PK was dose proportional up to 9.6 mg, T1/2 was 10 hours, and relative bioavailability of tablet formulation was excellent; major metabolite levels were low (<10%). Levels of CK18 fragments did not correlate with dose or tumor response. Stable disease (SD) lasting for 2-4 months was observed in 9 patients, among others in 4 of 4 mesothelioma and 2 of 2 ovarian pts. One additional pt with cholangiocarcinoma has ongoing SD lasting for 5 months. One of the ovarian pts had a significant decline of CA125 lasting for 3 months. Conclusions: The tablet formulation of BAY 1000394 was better tolerated than oral solution. So far, doses up to a 15 mg per day with concomitant antiemetic treatment showed an acceptable tolerability. SD was observed in 10 of 25 heavily pretreated pts across cohorts 3 – 8.

A phase I study of HM781-36B, a novel pan-HER inhibitor, in patients (pts) with advanced solid tumors.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3076-3076 ◽  
Author(s):  
Tae Min Kim ◽  
Keun-Wook Lee ◽  
Do-Youn Oh ◽  
Jong-Seok Lee ◽  
Seock-Ah Im ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Phase I Study ◽  
Advanced Solid Tumors ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Expansion Cohort ◽  
Positive Breast Cancer

3076 Background: HM781-36B is a pan-HER tyrosine kinase inhibitor, which showed a potent activity against the gefitinib- or erlotinib-resistant, EGFR L858R/T790M double mutant cells. A phase I study was conducted to determine the MTD, pharmacokinetics, and antitumor activity. Methods: Eligible pts had advanced malignancies refractory to standard therapies. Standard 3+3 scheme was used in the dose escalation part, and additional 12 pts were enrolled in the expansion cohort of molecular enrichment. Results: In dose-escalation part, 43 pts (median age: 55 yrs (range 25-82), M:F=25:18, ECOG PS 0/1/2/3: 23/17/2/1, median prior chemotherapy: 4) were treated. DLTs were G3 diarrheas in 5 pts, one at 12 mg, 16 mg, 24 mg, and two at 32 mg. The MTD was determined as 24mg. The most common drug-related adverse events were diarrhea, stomatitis, rash, pruritus, and anorexia. Among 41 evaluable pts, 4 pts achieved PR (1 unconfirmed, duration of response: 11.9 mo, 7.07 mo+, 4.5 mo+), and 19 pts had SD. Two of 4 PR pts were Her2-positive breast cancer pts. The median duration of treatment in pts with PR or SD was 3.87 (2.47- 15.17) months. In the dose range of 0.5 to 24 mg, it showed linear pharmacokinetics proportional to dose-escalation, relatively short half-life, and little accumulation. Additional 12 pts in the expansion cohort are under treatment at 24 mg (6 pts: EGFR-mutant NSCLC, 3 pts: Her2-positive gastric cancer, 2 pts: Her2-positive breast cancer, 1 pt: rectal cancer). Conclusions: HM781-36B was safe and well tolerable in advanced solid tumors. Preliminary evidence of anticancer activity has been observed. Updated data will be presented at the meeting.

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