A phase Ⅰ open-label dose-escalation study of AL2846 in combination with gemcitabine in patients with locally advanced or metastatic pancreatic adenocarcinoma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e16210-e16210
Author(s):  
Rui Liu ◽  
Ting Deng ◽  
Ming Bai ◽  
Le Zhang ◽  
Tao Ning ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Dose Level ◽  
Standard Dose ◽  
Locally Advanced ◽  
Maximum Tolerated Dose ◽  
Ductal Adenocarcinoma ◽  
Efficacy Evaluation ◽  
Dose Escalation Study ◽  
Grade 3 ◽  
Dose Levels

e16210 Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with a 5-year survival rate of 10%. Overexpression of c-Met is associated with the poor prognosis in patients with PDAC and it was noted that phosphorylation of c-Met is increased in gemcitabine-resistant PDAC. AL2846 is an oral c-Met inhibitor, which targets multiple receptor tyrosine kinases (RTK’s) primarily including c-Met, VEGFR1, KIT, Axl and RET. The combination of AL2846 with chemotherapy may improve the clinical efficacy of PDAC. Based on these consideration, a phase Ⅰ clinical trial was initiated to determine the maximum tolerated dose (MTD) of AL2846 in combination with gemcitabine in patients with advanced PDAC and to clarify the potential anti-tumor activity. Methods: Patients with untreated locally advanced or metastatic PDAC were enrolled to receive oral AL2846 once daily in a fasted state in combination with gemcitabine intravenous infusion over 30 min on days 1, 8, and 15 every 28 days. The starting dose level is AL2846 40 mg and gemcitabine 1000 mg/m2. Primary endpoint was the maximum tolerated dose (MTD), defined as the highest dose level at which ≤33 % of patients incurred a dose-limiting toxicity (DLT), and RP2D. Secondary endpoints included response rate (ORR), progression-free survival (PFS) and overall survival (OS). Results: As of January 1, 2021, a total of 15 patients with PDAC were enrolled and received 4 dose-levels of AL2846 (40 mg: n = 1; 60 mg: n = 6; 90 mg: n = 3; 120 mg: n = 5) treatment. DLTs occurred in 1 patient who experienced grade 3 abnormal liver function. The most common grade 3 or above drug-related adverse events were neutropenia (n = 7, 46.7%), thrombocytopenia (n = 5, 33.3%), leukopenia (n = 4, 26.7%), GGT increased (n = 4, 26.7%), hyperbilirubinemia (n = 3, 20.0%) and alkaline phosphatase increased (n = 3, 20.0%). Among the 15 patients available for efficacy evaluation, 1 patient (6.6%) achieved partial response who was at the dose levels of 90mg. There were 4 patients whose PFS was more than 5 months. Although there were no more than 2 DLT events, we chose 90 and 120 mg as the target dose for RP2D according to the dose reduction and proportion of gemcitabine. Conclusions: The RP2D of AL2846 in combination with standard dose of gemcitabine were 90 and 120 mg QD continuously. The results demonstrated that AL2846 in combination with gemcitabine was well tolerated at doses up to 120 mg. Further clinical studies about the efficacy of AL2846 in pancreatic cancer are in progress. Clinical trial information: CTR20201021.

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

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3564-3564
Author(s):  
Shubham Pant ◽  
Lowell L. Hart ◽  
Johanna C. Bendell ◽  
Jeffrey R. Infante ◽  
Suzanne Fields Jones ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Level ◽  
Phase I Study ◽  
Standard Dose ◽  
Maximum Tolerated Dose ◽  
Advanced Solid Tumors ◽  
Hsp90 Inhibition ◽  
Grade 3 ◽  
Dose Levels

3564 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. Preclinical evidence suggests potential synergy between HSP90 inhibition and fluorouracil. 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: Pts with refractory solid tumors received AUY922 with capecitabine in a standard 3+3 dose escalation. Dose levels were capecitabine 1000mg/m2 PO BID d 1-14 of 21-day cycles, with escalating doses of AUY922 IV 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 pts 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). No DLTs were observed until the 6th dose level (grade 3 diarrhea). Related adverse events (% grade 1/2; % grade 3/4) included: diarrhea (43%; 17%), fatigue (30%; 13%), nausea (39%; 0), hand-foot skin reaction (30%; 5%), anorexia (30%; 4%), vomiting (30%; 0), and darkening vision (26%; 0). Vision darkening, a class effect of HSP90 inhibitors, was reversible with drug hold and retreatment was possible. Two pts (9%) had hematologic G 3/4 events of neutropenia. Of the 19 pts evaluable for response, partial response was noted in 4 patients (colorectal, 2; breast, 1; stomach, 1); 2 had progressed on prior fluorouracil, and remained on treatment for 13-35 wks. Stable disease was noted in 8 pts (35% [colorectal, 5; pancreas, 2; breast, 1]) with a median duration of 25.5 wks (range: 11-44+). All 5 colorectal pts were refractory to 5-FU. Conclusions: The addition of AUY922 to standard dose capecitabine was well-tolerated at doses of up to 70mg/m2. Preliminary efficacy is encouraging, particularly as seen in pts previously resistant to fluorouracil, and warrants further investigation of this regimen. Clinical trial information: NCT01226732.

A Phase 1 Dose Escalation Study of a Fully Human, Antagonist Anti-CD40 Antibody, HCD122 (Formerly CHIR-12.12) in Patients with Relapsed and Refractory Multiple Myeloma.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3575-3575 ◽  
Author(s):  
William Bensinger ◽  
Sundar Jagannath ◽  
Pamela S. Becker ◽  
Kenneth C. Anderson ◽  
Edward A. Stadtmauer ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Dose Level ◽  
Ex Vivo ◽  
Phase 1 ◽  
Safety Evaluation ◽  
Median Number ◽  
Maximum Tolerated Dose ◽  
Dose Escalation Study ◽  
Myeloma Cells ◽  
Dose Levels

Abstract HCD122 is a novel, fully human, IgG1 antagonistic monoclonal antibody targeting the CD40 receptor. This antibody blocks CD40-mediated signaling and is a potent mediator of antibody-dependent cellular cytotoxicity (ADCC). Previous preclinical investigation confirmed expression of CD40 on myeloma cells in the majority of patients and reported antitumor activity of HCD122 against multiple myeloma cells ex vivo (Tai, Y et al. Cancer Res2005; 65(13): 5898–5906). This ongoing phase 1 study will determine the maximum tolerated dose of CHIR-12.12 in multiple myeloma patients (pts) who are relapsed or refractory after at least one prior therapy. Planned dose levels are 1, 3 and 10 mg/kg administered IV once weekly for 4 weeks. Each dose group will enroll 3–6 pts to evaluate safety, pharmacokinetics (PK) and clinical response. To date, 9 pts have been treated at 2 dose levels: 3 pts at 1 mg/kg and 6 pts at 3 mg/kg. Median patient age is 65 yrs (46–81 yrs); median number of prior therapies is 3 (2–12). No dose limiting toxicity (DLT) occurred at the 1mg/kg dose level. At 3 mg/kg, 1 DLT of grade 4 thrombocytopenia occurred in 1 pt. No other grade 3 and 4 lab abnormalities and adverse events have been reported. In 7 pts with available data, infusions were well tolerated, with easily managed grade 1–2 toxicities, primarily chills (5 pts), nausea (3 pts), pyrexia (2 pts), and arthralgia (2 pts) mainly reported during the first infusion. Preliminary PK analysis showed more than dose proportional - increase in Cmax and AUC at the 3 mg/kg dose level compared to the 1 mg/kg dose level. At the 3 mg/kg dose, antibody accumulation occurred week-to-week; the mean Cmax after the fourth infusion on Day 22 was 126.1 mg/mL(range 52 – 195 ug/mL) and HCD122 levels were measurable up to Day 57 and in one patient up to Day 99. One week after the last 3 mg/kg dose, trough levels ranged from 28 to 109 mg/mL. Of the 3 pts at 1 mg/kg, one showed stable disease (SD) for >23 weeks and two had progressive disease (PD) by week 5. Of the 6 pts at 3 mg/kg, one had partial response (PR) at week 9 and was confirmed at week 15, one had SD for > 5 weeks, and 4 had PD at week 5. One pt with PD terminated the study before final safety evaluation, and must be replaced before assessment of the 3mg/kg dose level is complete. Thus, in preliminary studies, HCD122 appears to be safe and well tolerated to date at doses of 1 mg/kg and 3 mg/kg weekly for 4 doses and shows promising anti-myeloma activity. Enrollment is continuing to determine MTD.

Phase I-II Trial of Oral Cyclophosphamide, Prednisone and Lenalidomide (Revlimid®) (CPR) for the Treatment of Patients with Relapsed and Refractory Multiple Myeloma.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1723-1723
Author(s):  
Donna E. Reece ◽  
Esther Masih-Khan ◽  
Arooj Khan ◽  
Peter Anglin ◽  
Christine Chen ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Dose Level ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Oral Cyclophosphamide ◽  
Varicella Zoster ◽  
Refractory Multiple Myeloma ◽  
Grade 3 ◽  
Dose Levels

Abstract Oral cyclophosphamide and prednisone is a convenient regimen in relapsed and refractory multiple myeloma (MM), with a partial response (PR) rate of 40% and median progression-free survival of 19 months in our retrospective analysis of patients in first or second relapse after autologous stem cell transplantation (ASCT) (Trieu Y, et al, Mayo Clin Proc2005; 80: 1582). We sought to enhance the efficacy of this regimen by adding oral lenalidomide (Revlimid®), a potent anti-myeloma agent, in a phase I-II trial. The CPR regimen consisted of cyclophosphamide on days 1, 8 and 15, lenalidomide on days 1–21, and prednisone 100 mg every other day in a 28-day cycle. ASA 81 mg/day was given to all patients (pts) as prophylaxis for DVT. Three dose levels were evaluated using a 3 by 3 dose escalation design. Between 11/2007–07/2008, 15 pts with relapsed/refractory MM were entered onto study. Median age was 60 (45–78) years and 60% were male. Immunoglobulin subtype was IgGκ:λ in 10:1; IgA κ:λ in 2:1 and κ light chain in 1. Median number of prior regimens was 2 (1–3) and 14 had undergone previous ASCT, including double transplants in 2 pts. Prior therapy also included thalidomide in 3 (20%) and bortezomib in 6 (40%). FISH cytogenetics were available in 9, but none had 13q deletion, t(4;14) or p53 deletion. At the time of protocol entry, median β2-microglobulin level was 222 (92–325) nm/L, albumin 38 (35–46) g/L, creatinine 78 (50–100) μmol/L, platelet count 230 (93–318) x 109/L and ANC 2.5 (1.9–9.0) x 109/L. Protocol treatment is summarized in Table 1. Dose level N Cyclophosphamide dose (mg/m2) Lenalidomide dose (mg) Prednisone dose (mg) Median # cycles given 1 3 150 15 100 9 2 3 150 25 100 6 3 6 300 25 100 4 3 (expanded) 3 300 25 100 1 Dose limiting toxicity was not observed during cycle 1 at any of the dose levels and the maximum tolerated dose of this regimen has not yet been reached at the highest dose level planned; all pts remain on active therapy. Grade 3/4 thrombocytopenia was seen in 1 pt (cohort 2) and neutropenia in 4 pts (1 in cohort 1, 1 in cohort 2 and 2 in cohort 3) and were managed with dose reduction and/or growth factor support. No episodes of febrile neutropenia occurred in any pt. Only 1 pt experienced varicella zoster; routine antiviral prophylaxis was not used. Other grade 3/4 non-hematologic toxicities were uncommon and included abdominal pain/bacteremia in 1 pt in cohort 1, hypokalemia in 1 pt in cohort 2, and DVT in 1 pt in cohort 3. Mild grade 1/2 constipation (47%), muscle cramps (33%) and fatigue (33%) were also noted. To date, best response includes the following: dose level 1 (1 near complete remission [nCR], 2 PR); dose level 2 (3 PR); dose level 3 (4 PR, 2 minimal response [MR]); expanded cohort 3 (1 MR, 2 too early). We conclude: 1) the combination of full doses of the agents in CPR can be given in a 28-day cycle with minimal toxicity; 2) the overall response rate (nCR + PR + MR) in 13 evaluable pts to date is 87%; 3) no pts have progressed in this preliminary analysis; 4) longer follow-up is required to assess the long-term efficacy of this regimen.

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]

Final results of a phase I trial of chemotherapy combination with docetaxel, cisplatin, and S-1 (TPS) in patients with locally advanced or recurrent metastatic head and neck cancer (HNC)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 6021-6021
Author(s):  
M. Tahara ◽  
K. Araki ◽  
N. Kiyota ◽  
S. Okano ◽  
N. Fuse ◽  
...  
Keyword(s):  
Head And Neck Cancer ◽  
Head And Neck ◽  
Dose Level ◽  
Neck Cancer ◽  
Response Rate ◽  
Metastatic Cancer ◽  
Locally Advanced ◽  
Maximum Tolerated Dose ◽  
Eligibility Criteria ◽  
Grade 3

6021 Background: An oral fluoropyrimidine, S-1, has shown high efficacy against head and neck cancer (HNC), with a response rate of 34%. We investigated the maximum tolerated dose (MTD) of combination therapy with docetaxel, cisplatin and S-1 (TPS) in patients (pts) with locally advanced or recurrent/metastatic HNC. Methods: Eligibility criteria were histologically proven HNC, PS 0–1, age ≤75 years, adequate organ function, and no prior chemotherapy. Treatment consisted of 1-hour infusion of docetaxel at escalating doses of 50, 60 and 70 mg/m2, 2-hour infusion of cisplatin at 70 mg/m2/day on day 1, and S-1 twice daily on days 1–14 at escalating doses of 40, 60, and 80 mg/m2/day. This regimen was repeated every 3 or 4 weeks. Pts with locally advanced HNC received concurrent chemoradiotherapy after completion of 3 cycles of TPS. Results: Forty pts were enrolled, consisting of 33 males and 7 females with a median age of 50 years (range 22–74 years). Twenty-nine cases were locally advanced cancer and 11 were metastatic cancer. 116 cycles (median = 3, range 1–6) were administered in 6 dose levels. Grade 3 or 4 hematological toxicities were neutropenia (59%), febrile neutropenia (13%), and anemia (8%), whereas no grade 3 or 4 thrombocytopenia was seen. Two dose-limiting toxicities (DLTs) were observed at dose level 5 (TPS: 70/70/80 mg/m2/day every 3 weeks), namely one grade 3 infection and one grade 3 hyperbilirubinemia, establishing this as the MTD. Of 12 pts treated at dose level 6 (TPS: 70/70/60 mg/m2/day every 3 weeks), three DLTs were seen, namely one grade 3 diarrhea, one grade 3 ALT/AST and one grade 2 creatinine elevation. Of a total of 40 pts, 6 achieved a complete response and 22 a partial response according to RECIST, giving an overall response rate of 70%. Conclusions: The TPS combination was well tolerated. The recommended phase II dose was determined to be TPS at 70/70/60 mg/m2/day every 3 weeks. Antitumor activity was highly promising, and warrants further investigation. No significant financial relationships to disclose.

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.

Concurrent treatment with everolimus (RAD001) and hormonoradiotherapy in high-risk locally advanced prostate cancer: Results of a phase I trial.

2013 ◽  
Vol 31 (6_suppl) ◽  
pp. 150-150 ◽  
Author(s):  
David Azria ◽  
Xavier Rebillard ◽  
Nathalie Coux ◽  
Marta Jarlier ◽  
Rodolphe Thuret ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
High Risk ◽  
Phase I ◽  
Dose Level ◽  
Advanced Prostate Cancer ◽  
Phase I Trial ◽  
Locally Advanced ◽  
Locally Advanced Prostate Cancer ◽  
Grade 3 ◽  
Dose Levels

150 Background: Everolimus is able to stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. Giving everolimus together with hormonotherapy and radiation therapy may kill more tumor cells. Methods: We conducted a phase I trial to evaluate the impact of everolimus (RAD001), an mTOR inhibitor, in patients treated concurrently with radiotherapy (RT) and ablative androgen treatment in high-risk locally advanced prostate cancer. Inclusion criteria were high-risk locally advanced non metastatic prostate cancer defined as clinical stage ≥ T3 or Gleason score ≥ 8 or PSA ≥ 20. The week before the beginning of RT, RAD001 was administered at different dose levels, twice daily, until the last day of irradiation. A nonsteroid antiandrogen was also given for 1 month at the beginning of RT. Prostate and seminal vesicle were irradiated up to 74Gy in 37 fractions of 2Gy with concomitant long-term LHRH analogue. The starting dose of RAD001 was 5mg/d with subsequent dose levels of 7.5 and 10 mg/d. The primary endpoint was the determination of the maximum tolerated dose (MTD). Dose escalation was implemented according to the continual reassessment method (CRM). Results: Fifteen patients were enrolled and 14 were assessable for toxicity and response. Significant toxicities were demonstrated at the 7.5 and 10 mg/d dose levels. Dose-limiting toxicity (DLT) occurred in two patients at dose level 7.5 mg/d and characterized by a grade 3 diarrhea and a grade 3 hydronephrosis due to dehydration and kidney lithiasis. DLT also occurred in two patients at dose level 10 mg/d (grade 3 diarrhea and grade 3 laryngopharyngeal infection). The MTD was reached at 7.5 mg/day (dose-level II). The recommended dose of RAD001 was 5 mg/d. After a median follow-up of 22 months, 12 patients are alive, 1 is dead (not related to cancer) and 2 patients had relapsed. Conclusions: Concomitant hormone-radiotherapy and everolimus is well-tolerated with mucositis, hypercholesterolemia, and urinary disorders. The recommended phase-II trial dose of everolimus in this combined setting is 5 mg/day. Clinical trial information: NCT00943956.

A phase I dose escalation study of SCB01A, a micro-tubular inhibitor with vascular disrupting activity, in patients with advanced solid tumors refractory to standard therapy.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 2531-2531 ◽  
Author(s):  
Nai-Jung Chiang ◽  
Her-Shyong Shiah ◽  
Chia-Chi Lin ◽  
Chia-Jui Yen ◽  
Hui-Jen Tsai ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Phase I ◽  
Solid Tumor ◽  
Safety Concern ◽  
Lower Limbs ◽  
Open Label ◽  
Dose Escalation Study ◽  
Grade 3 ◽  
Dose Levels ◽  
Vascular Disrupting

2531 Background: SCB01A is a novel anti-microtubular agent with vascular disrupting activity. The Phase I study aimed to determine the dose-limiting toxicity (DLT), maximum tolerated dose (MTD), safety, and pharmacokinetic (PK) profiles of SCB01A in patients with advanced solid tumor. Methods: This was an open-label, phase I clinical trial with a rapid titration followed by a 3 x 3 study design. Eligible patients would receive a 3-hr intravenous infusion of SCB01A, every 21 days as one cycle. All adverse events were classified according to the CTCAE V4.0. DLT was defined as the occurrence of grade 3 with complications and grade 4 hematoloigcal, or ≥grade 3 non-hematological toxicities. Results: From June 2011 to November 2015, a total of 33 eligible patients were enrolled to eight dose levels: 2 mg/m2 (n = 1), 3 mg/m2 (n = 1), 4 mg/m2 (n = 6), 6.5 mg/m2 (n = 9, with 3 additional subjects were recruited for safety concern), 10 mg/m2 (n = 3), 16 mg/m2 (n = 3), 24 mg/m2 (n = 6) and 32 mg/m2 (n = 4). Six episodes of DLTs were observed in 5 patients (each one in dose levels of 4/6.5/24 mg/m2 and two in dose level of 32 mg/m2), including grade 4 blood creatine phosphokinase elevation (4 mg/m2), grade 3 gastric hemorrhage (6.5 mg/m2), grade 2 venous thrombosis (24 mg/m2), grade 3 peripheral neuropathy manifested as weakness of lower limbs, grade 3 aspartate aminotransferase elevation, and grade 3 hypertension (32 mg/m2). The MTD was determined to be 24 mg/m2. Pharmacokinetic profiles revealed a linear AUC-dose response with an average elimination half-life (t1/2) of 2.5 hours. Partial response was observed in one subject with buccal cancer. A total of 57.6% (19/33) subjects had stable disease for at least 2 cycles. Conclusions: SCB01A is safe and tolerable in patients with solid tumor. The MTD of SCB01A is 24 mg/m2 every 21 days, which deserves further development. Clinical trial information: NCT011159522.

Phase I trial of radiotherapy with concurrent bevacizumab, erlotinib, and capecitabine for locally advanced pancreatic cancer (LAPC).

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 254-254
Author(s):  
Heath Devin Skinner ◽  
Milind M. Javle ◽  
Robert A. Wolff ◽  
Marilyn V. Clemons ◽  
Mark F. Munsell ◽  
...  
Keyword(s):  
Median Survival ◽  
Locally Advanced ◽  
Advanced Pancreatic Cancer ◽  
Growth Factor Receptor ◽  
Complete Response ◽  
Maximum Tolerated Dose ◽  
High Rate ◽  
Viable Tumor ◽  
Grade 3 ◽  
Dose Levels

254 Background: The addition of bevacizumab to capecitabine-based chemoradiotherapy (CRT) for LAPC has been shown to be safe. The aim of this study was to determine the safety, tolerability and maximum tolerated dose (MTD) of the addition of erlotinib to this treatment regimen. Methods: Seventeen patients with CT-staged biopsy-proven non-metastatic unresectable LAPC were enrolled between March 2008 and October 2010. Prior chemotherapy was permitted. All patients received 50.4 Gy (GTV only) in 28 fractions with concurrent capecitabine, bevacizumab and erlotinib. Dose was escalated using a continual reassessment method. Two patients each were enrolled at dose levels (DLs) 1-4 and 9 patients at DL 5. Bevacizumab was escalated from 5mg/Kg every two weeks (DLs 1-4) to 10mg/Kg (DL 5); erlotinib from 100 mg/day (DLs 1-2) to 150 mg/day (DLs 3-5); and capecitabine from 400mg/m2 twice daily on days of radiation (DL 1) to 600mg/m2 (DLs 2-3) to 825 mg/m2 (DLs 4-5). Reassessment for potential resection was performed 6-8 weeks later. Results: With a median follow-up of 10 months (range 3-23), no grade 3 toxicities were observed in DLs 1-4. Three (33%) patients at DL 5 developed a grade 3 acute toxicity (2 diarrheas and 1 rash). No grade 4 or 5 toxicities were seen. DL 4, with a posterior probability of 0.122 of dose limiting toxicity, was selected as the MTD. Median survival was 19.4 months and time to distant progression was 9.8 months. Patients treated at DLs 4 and 5 had a median survival of 24 months. Of 5 patients who underwent margin-negative resections, 4 were originally deemed unresectable and 1 was borderline; 4 were treated at DLs 4 or 5 (36% of patients treated at these DLs); 3 patients had excellent pathological responses (complete response, 5% viable tumor, and 20% viable tumor) at pancreatectomy and are alive at 13, 21 and 22 months respectively with no local or distant failures. Conclusions: The combination of erlotinib, bevacizumab and capecitabine with radiotherapy for LAPC is safe and tolerable. Both the promising survival and the high rate of resectability at the higher dose levels suggest that this strategy of dual inhibition of growth factor receptor pathways during CRT warrants continued evaluation.

Early safety from a phase 1, multicenter, open-label clinical trial of talimogene laherparepvec (T-VEC) injected into liver tumors.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 438-438 ◽  
Author(s):  
J. Randolph Hecht ◽  
Miklos Pless ◽  
Antonio Cubillo ◽  
Aitana Calvo ◽  
Steven Raman ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Liver Tumors ◽  
Disease Incidence ◽  
Phase 1 ◽  
Cell Cancer ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Open Label ◽  
Dose Escalation Study ◽  
Grade 3

438 Background: T-VEC is a genetically modified HSV-1 oncolytic immunotherapy designed to preferentially replicate in tumors, produce GM-CSF, and stimulate anti-tumor immune responses. This study evaluates the safety of intrahepatic injection (inj) of T-VEC in patients (pts) with hepatocellular carcinoma (HCC) or liver metastases (mets). Methods: The primary objective is to assess the maximum tolerated dose. Eligible pts were ≥ 18 years (y) old, had progressive HCC or breast cancer (BC), colorectal cancer (CRC), gastroesophageal cancer, melanoma, non-small cell lung cancer, or renal cell cancer with liver mets, with measurable liver tumors suitable for inj. This dose escalation study comprised 2 groups: A (non-HCC) and B (HCC). T-VEC was given initially at 106 plaque-forming units (PFU)/mL followed by up to 4 mL of 107 PFU/mL (cohort 1) or 108 PFU/mL (cohort 2) every 21 (±3) days (Q21D), or up to 8 mL of the maximum tolerated concentration (MTC) Q21D (cohort 3). Inj volume was based on lesion size. Results: Results from cohorts 1 and 2 of group A are reported. 14 pts were treated; 12 (3 BC, 9 CRC) were DLT-evaluable: Median age was 65.5 y (range: 33, 73); median number of inj was 3; 1 pt received all 12 inj. MTC was 108 PFU/mL. There was 1 DLT, grade 3 aspartate aminotransferase (AST)/grade 2 bilirubin increase (inc), after 1 dose. In all treated pts, 4 (28.6%) had grade 3/4 treatment-related adverse events (TRAEs): anemia and inc gamma-glutamyltransferase, alanine aminotransferase (ALT), and AST. There were 2 deaths attributable to disease. Incidence of serious AEs (SAEs) is shown (Table). Conclusions: The MTC was 108 PFU/mL Q21D after initial inj at 106 PFU/mL. Repeated intrahepatic inj of T-VEC at the FDA-approved concentration for intralesional inj of melanoma was deemed tolerable and feasible in pts with liver mets. Additional investigation in combination with a PD-1 inhibitor is planned. Clinical trial information: NCT02509507. [Table: see text]

Sign in / Sign up

Export Citation Format

Share Document