A phase I study of 17-AAG in relapsed/refractory pediatric patients with solid tumors: A Children’s Oncology Groups study

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 9018-9018 ◽  
Author(s):  
B. Weigel ◽  
S. Blaney ◽  
J. Kersey ◽  
R. Bagatell ◽  
S. P. Ivy ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Dose Escalation ◽  
Phase I Study ◽  
Drug Exposure ◽  
Mononuclear Cells ◽  
Surrogate Marker ◽  
Hsp90 Inhibition ◽  
Recommended Phase Ii Dose ◽  
Dose Levels

9018 Background: A pediatric phase I study of 17-allylaminogeldanamycin (17-AAG), an Hsp90 inhibitor, was conducted to determine the dose limiting toxicities (DLTs), the recommended phase II dose, the pharmacokinetics (PK), and to evaluate a surrogate marker for Hsp90 inhibition in peripheral blood mononuclear cells (PBMCs). Methods: Cohorts of 3–6 pts were enrolled at dose levels of 150, 200, 270 and 360 mg/m2/dose, administered as a 60 min infusion, on days 1, 4, 8 and 11 of a 21-day cycle. PK and PBMC evaluations were done during the first course of therapy. Results: 17 pts (7 male), median 7 yrs of age (range 1–19), were enrolled. 5 pts who developed PD prior to completing a full cycle of therapy were not considered evaluable for toxicity. No DLTs occurred. Non-DLTs included elevated transaminases (n=6), anemia (n=3), and vomiting (n=3). Based on the adult recommended dose and challenges posed by infusing the large volumes of DMSO, dose escalation was stopped at dose level 4. No CRs or PRs were observed; 3 patients remain on therapy at 6, 7 and 9 months with SD. One patient with hepatoblastoma had a reduction in AFP and SD over 3 cycles. PK data is available from the initial 3 dose levels. Drug exposure increases in proportion to dose for both17-AAG and its metabolite 17-AG. At 270 mg/m2/dose the Cmax and AUC of 17-AAG were 5,303 ± 1,591 ng/ml and 13,150 ± 5,086 ng/ml*hr, respectively, similar to the exposure in adults. The mean terminal half-life for 17-AAG was 3.0 ± 0.5 hrs. Induction of Hsp72, a surrogate marker for inhibition of Hsp90 was detected at all dose levels. Conclusions: The recommended phase II dose of 17AAG is 360mg/m2/day. Non-DMSO formulations may allow for further dose escalation in children and should be studied. No significant financial relationships to disclose.

Phase I study of temsirolimus (CCI-779), carboplatin, and paclitaxel in patients (pts) with advanced solid tumors: NCIC CTG IND 179

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 3558-3558
Author(s):  
A. M. Oza ◽  
C. Kollmannsberger ◽  
H. Hirte ◽  
S. Welch ◽  
L. Siu ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Phase Ii ◽  
Phase I Study ◽  
Solid Malignancies ◽  
Recommended Phase Ii Dose ◽  
Dose Levels ◽  
Further Development ◽  
Dose Limiting Toxicity

3558 Background: Temsirolimus (T) has encouraging activity in many malignancies, including endometrial cancer and a combination with carboplatin and paclitaxel would logical regimen for further development. This trial was designed to assess the safety and tolerability of this combination and expand experience at the recommended dose in pts with endometrial and ovarian cancers. Methods: A 3+3 dose escalation Phase I study has been conducted in pts with advanced solid malignancies suitable for carboplatin and paclitaxel chemotherapy who had not received more than 2 prior lines of chemotherapy. To date, 31 eligible pts with a median age of 59 have been treated and 27 are evaluable for toxicity. Pts were entered in 6 dose levels, with the first two levels administering T on Days 8 and 15 and the next 4 levels switching to a D1, 8 administration. Eighteen had received prior chemotherapy and 15 prior radiation. Results: Day 8, 15 administration of T was not feasible due to myelosuppression on day 15. The combination of carboplatin and paclitaxel on day 1 with T on D1 and 8 has been well tolerated, and patients have received a median of 5 cycles of therapy. At dose level 6 (T 25 mg D1 and 8, paclitaxel 175 mg/m2 D1, carboplatin AUC 6 D1) dose limiting toxicity (DLT) was seen in one of 6 pts treated to date (Gr 4 thrombocytopenia) and a second pt had a possible DLT ( Gr 3 fatigue in presence of baseline fatigue). This dose level is being expanded in 4 endometrial and ovarian cancer pts. The regimen is active: of the 26 patients with follow-up data, there have been 10 with partial response (38.5%; med. duration 7.1 mo [1.0–12.7]) and 12 with stable disease (46%; med. duration 6.9 mo [1.3- 7.8]). One patient had progressive disease and three were inevaluable. Conclusions: The results indicate this combination is well tolerated and requires additional assessment in a Phase II setting. The recommended Phase II dose will be dose level 6 provided no further DLTs are observed in the additional 4 patients entered. [Table: see text] No significant financial relationships to disclose.

Phase I study of vinorelbine, cisplatin, and concomitant thoracic radiation in the treatment of advanced chest malignancies.

1998 ◽  
Vol 16 (6) ◽  
pp. 2157-2163 ◽  
Author(s):  
G A Masters ◽  
D J Haraf ◽  
P C Hoffman ◽  
L C Drinkard ◽  
S A Krauss ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Phase I Study ◽  
Maximum Tolerated Dose ◽  
Concurrent Chemotherapy ◽  
Unresectable Stage ◽  
Thoracic Radiation ◽  
Recommended Phase Ii Dose ◽  
Group B ◽  
Dose Levels

PURPOSE The cisplatin-vinorelbine regimen has superior activity in advanced non-small-cell lung cancer (NSCLC). We conducted a phase I trial to identify the maximum-tolerated dose (MTD) and dose-limiting toxicities (DLTs) of this regimen with concomitant thoracic radiation (RT) in patients with advanced chest malignancies. PATIENTS AND METHODS Patients with advanced chest malignancies that required RT were enrolled onto this phase I study of standard chest radiation (30 daily 2-Gy fractions for a total of 60 Gy) and concurrent chemotherapy with cisplatin starting at 100 mg/m2 every 3 weeks and vinorelbine starting at 20 mg/m2/wk. RESULTS Thirty-seven patients were treated on this study. Two of three patients treated at the maximum-administered dose of cisplatin 100 mg/m2 per cycle and vinorelbine 25 mg/m2/wk experienced acute DLT (neutropenia), which required deescalation. The dose level of cisplatin 100 mg/m2 and vinorelbine 20 mg/m2/wk, although tolerated acutely, produced delayed esophagitis, which proved dose-limiting. The recommended phase II dose was cisplatin 80 mg/m2 every 3 weeks and vinorelbine 15 mg/m2 given 2 of every 3 weeks with concomitant chest RT. CONCLUSION Concomitant chemoradiotherapy with cisplatin and vinorelbine is feasible. The recommended phase II dose is cisplatin 80 mg/m2 every 3 weeks with vinorelbine 15 mg/m2 given twice over 3 weeks on a day 1/day 8 schedule. Esophagitis is the DLT, with neutropenia occurring at higher dose levels. A Cancer and Leukemia Group B (CALGB) phase II trial is currently underway to evaluate further the efficacy and toxicities of this regimen in unresectable stage III NSCLC.

scholarly journals Phase I study of ABBV-428, a mesothelin-CD40 bispecific, in patients with advanced solid tumors

2021 ◽  
Vol 9 (2) ◽  
pp. e002015 ◽  
Author(s):  
Jason J Luke ◽  
Fabrice Barlesi ◽  
Ki Chung ◽  
Anthony W Tolcher ◽  
Karen Kelly ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Phase I ◽  
Solid Tumors ◽  
Phase Ii ◽  
Dose Escalation ◽  
Phase I Study ◽  
Bispecific Antibody ◽  
Advanced Solid Tumors ◽  
Recommended Phase Ii Dose ◽  
Dose Proportional

BackgroundCD40 agonist immunotherapy can potentially license antigen-presenting cells to promote antitumor T-cell activation and re-educate macrophages to destroy tumor stroma. Systemic administration of CD40 agonists has historically been associated with considerable toxicity, providing the rationale for development of tumor-targeted immunomodulators to improve clinical safety and efficacy. This phase I study assessed the safety, tolerability, preliminary antitumor activity, and preliminary biomarkers of ABBV-428, a first-in-class, mesothelin-targeted, bispecific antibody designed for tumor microenvironment-dependent CD40 activation with limited systemic toxicity.MethodsABBV-428 was administered intravenously every 2 weeks to patients with advanced solid tumors. An accelerated titration (starting at a 0.01 mg/kg dose) and a 3+3 dose escalation scheme were used, followed by recommended phase II dose cohort expansions in ovarian cancer and mesothelioma, tumor types associated with high mesothelin expression.ResultsFifty-nine patients were treated at doses between 0.01 and 3.6 mg/kg. The maximum tolerated dose was not reached, and 3.6 mg/kg was selected as the recommended phase II dose. Seven patients (12%) reported infusion-related reactions. Treatment-related grade ≥3 treatment-emergent adverse events were pericardial effusion, colitis, infusion-related reaction, and pleural effusion (n=1 each, 2%), with no cytokine release syndrome reported. The pharmacokinetic profile demonstrated roughly dose-proportional increases in exposure from 0.4 to 3.6 mg/kg. Best response was stable disease in 9/25 patients (36%) treated at the recommended phase II dose. CD40 receptor occupancy >90% was observed on peripheral B-cells starting from 0.8 mg/kg; however, no consistent changes from baseline in intratumoral CD8+ T-cells, programmed death ligand-1 (PD-L1+) cells, or immune-related gene expression were detected post-ABBV-428 treatment (cycle 2, day 1). Mesothelin membrane staining showed greater correlation with progression-free survival in ovarian cancer and mesothelioma than in the broader dose escalation population.ConclusionsABBV-428 monotherapy exhibited dose-proportional pharmacokinetics and an acceptable safety profile, particularly for toxicities characteristic of CD40 agonism, illustrating that utilization of a tumor-targeted, bispecific antibody can improve the safety of CD40 agonism as a therapeutic approach. ABBV-428 monotherapy had minimal clinical activity in dose escalation and in a small expansion cohort of patients with advanced mesothelioma or ovarian cancer.Trial registration numberNCT02955251.

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

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 12007-12007
Author(s):  
R. A. Kosloff ◽  
J. Wright ◽  
P. Ivy ◽  
J. Escalon ◽  
B. Norwood ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Phase I Study ◽  
Major Contributor ◽  
Organ Function ◽  
Dose Escalation Study ◽  
Adequate Organ Function ◽  
Dose Levels ◽  
Platinum Agents

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

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

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 13026-13026 ◽  
Author(s):  
R. C. Donehower ◽  
A. Jimeno ◽  
J. Li PhD ◽  
K. Galvin ◽  
F. Anthony ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Antitumor Activity ◽  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Cross Resistance ◽  
Dose Escalation Study ◽  
Cell Cycle Inhibitor ◽  
Recommended Phase Ii Dose ◽  
Dose Levels

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

Phase I/II trial of combination nab-paclitaxel and pemetrexed in advanced solid tumor patients (pts) with emphasis on non-small cell lung cancer (NSCLC).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e19147-e19147
Author(s):  
Jonathan Riess ◽  
Cheryl Ho ◽  
Angela M. Davies ◽  
Derick Lau ◽  
Primo Lara ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Dose Escalation ◽  
Advanced Nsclc ◽  
Patient Characteristics ◽  
Maximum Tolerated Dose ◽  
Prior Therapy ◽  
Early Closure ◽  
Grade 3 ◽  
Recommended Phase Ii Dose

e19147 Background: Despite advances in targeted therapies, there is an ongoing need to develop new and effective cytotoxic drug combinations in NSCLC. Preclinical evaluation has demonstrated additive cytotoxicity of pemetrexed and taxanes. We evaluated the safety and efficacy of combining nab-paclitaxel (nP) and pemetrexed (P) in solid tumors with a focus on NSCLC for the phase II expansion. Methods: A 3+3 dose-escalation design was used to determine the maximum tolerated dose (MTD) and the recommended phase II dose (RP2D). Three dose levels were tested: P 500 mg/m2 day 1 plus nP on day 1 at doses of 180, 220, and 260 mg/m2 every 21 days. Dose limiting toxicity (DLT) in cycle 1 was defined as: grade 4 platelets or grade 3 platelets with bleeding, neutropenia with fever or documented infection, or other grade ≥ 3 non-heme toxicity. Phase II eligibility included advanced NSCLC, ≤ 2 line prior therapy, PS 0-1, adequate organ function. Primary endpoint for further study was response rate (RR) ≥ 25%. Results: Planned dose escalation during the Phase I portion was completed without reaching the MTD. The RP2D was P 500 mg/m2 and nP 260 mg/m2. The phase II portion accrued 37 pts before early closure due to increasing use of first-line pemetrexed/platinum doublet therapy in non-squamous NSCLC. Phase II patient characteristics: median 63 (45-77); M:F 23:14; median cycles 3. In 31 assessable patients: 5 PR, 12 SD and 14 PD. Efficacy: RR =14%; disease control rate (DCR) = 46%; median survival time (MST) = 8.7 months. Pts in the DCR group had a MST of 15.4 vs 4 months in the PD group (p=0.02). Conclusions: P 500 mg/m2 day 1 with nP 260 mg/m2 was feasible and well tolerated. The phase II component demonstrated activity in second-line therapy of advanced NSCLC. Practice patterns have evolved; so further trials of this regimen are not planned. Clinical trial information: NCT00470548.

Phase I/II trial of gemcitabine (Gem) plus irinotecan (CPT-11) for metastatic pancreatic cancer (MPC).

2014 ◽  
Vol 32 (3_suppl) ◽  
pp. 301-301
Author(s):  
Takuo Yamai ◽  
Tatsuya Ioka ◽  
Hironari Sueyoshi ◽  
Ryoji Takada ◽  
Nobuyasu Fukutake ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Overall Survival ◽  
Phase I ◽  
Phase Ii ◽  
Combination Chemotherapy ◽  
Phase I Study ◽  
Progressive Disease ◽  
Metastatic Pancreatic Cancer ◽  
Refractory Ascites ◽  
Recommended Phase Ii Dose

301 Background: Treatment options for patients with metastatic pancreatic cancer are still limited. Recently, new strategies to prolong disease control are reported. We conducted phase I/II trial of GEM+CPT-11 combination chemotherapy for MPC to evaluate the effectiveness and safety. Methods: As phase I study, traditional 3 + 3 dose-escalation design was used to determine the maximum tolerated dose (MTD) and the recommended phase II dose. Four escalating dose levels of GEM/CPT-11 (800/60 mg/m2, 1000/60 mg/m2, 1000/80 mg/m2, and 1000/100 mg/m2) were studied. As results of this investigation, the recommended phase II dose was GEM 1000 mg/m2 and CPT-11 100 mg/m2, biweekly. Phase II eligibility included naïve MPC, PS0-2, Pathological diagnosis, no refractory ascites and pleural effusion, and adequate organ function. Primary endpoint was overall survival. Results: Eighteen patients were entered phase I study. The DLTs were anorexia, and nausea/vomiting. Severe neutropenia was rare. MTDs were determined GEM 1000 and CPT-11 100 mg/m2. After that, we investigated phase II trial in 40 patients. There were 6 partial response, 14 stable disease, 18 progressive disease and 2 in-evaluable. Response rate was 16%. The median overall survival was 7.5 months; progressive disease 4.0 months. Grade 3 to 4 toxicity included neutropenia (7%), anemia (7%), diarrhea (7%), ALT elevation (10%), pneumonitis(7%). There was no treatment-related death. Conclusions: This combination chemotherapy is not effective as first-line chemotherapy for metastatic pancreatic cancer. But this is safe and generally well tolerated. This chemotherapy could be effective of salvage chemotherapy with low toxicity after standard chemotherapy such as FOLFIRINOX.

A phase I study of veliparib (Vel) in combination with oxaliplatin (Ox) and capecitabine (Cap) in advanced solid tumors.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 314-314 ◽  
Author(s):  
Anita Ahmed Turk ◽  
Dustin A. Deming ◽  
Sam Joseph Lubner ◽  
Daniel Mulkerin ◽  
Noelle K. LoConte ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
Phase I Study ◽  
Brca Mutation ◽  
Parp Inhibition ◽  
Eligibility Criteria ◽  
Strand Breaks ◽  
Platinum Based Chemotherapy ◽  
Dna Strand ◽  
Recommended Phase Ii Dose

314 Background: Poly(ADP-ribose) polymerases (PARP) are activated by DNA strand breaks and important for DNA repair in response to platinum-based chemotherapy. PARP inhibition with Vel might enhance anti-tumor effects of Cap with Ox. This phase I study (NCI 8604) examines the tolerability, safety and preliminary efficacy of the combination of Vel with Cap and Ox. Methods: This is a phase I dose escalation protocol testing escalating doses of Vel with Cap and Ox every 28 days (Table 1). Pts were treated in cohorts of 3-6 pts until cycle 1 DLTs were defined. Key eligibility criteria included age ≥ 18 with histologically confirmed malignancy meeting at least one of the following: documented BRCA1/2 mutation and a BRCA related malignancy; a 20% probability of harboring a BRCA mutation; metastatic colorectal cancer; mucinous ovarian cancer; other GI malignancy in which Ox has demonstrated activity. Results: 17 pts (median age 52 [range 19-71]; 14 female, 3 male) were treated at 4 dose levels (DL) (Table 1). Pts had cholangiocarcinoma (6), breast (4), ovarian (4), neuroendocrine (1), pancreas (1), and colon (1) cancers. 7 pts (4 breast, 3 ovarian) are BRCA1+. Dose escalation was initiated at DL1. One DLT (mucositis) occurred at this dose level. At DL2, two DLTs (mucositis with neutropenic fever and thrombocytopenia) were noted. The protocol was amended for escalation to begin at DL1A. At DL2A, a grade 2 DLT of fatigue requiring dose delay occurred in one pt. Pts were on study for median 10 weeks (range 1 – 88). 24% of pts remained on study ≥ 6 months. Of the 14 pts with measurable disease, 5 had PR (2 ovarian, 2 breast, 1 colon) and 4 had SD (3 cholangiocarcinoma, 1 pancreas). Common AEs include nausea/vomiting (94%), diarrhea (47%), mucositis (41%), anemia (35%), neutropenia (24%), and thrombocytopenia (18%). Conclusions: Vel in combination with Cap and Ox is safe and well tolerated in pts with advanced solid malignancies. The recommended phase II dose is DL2A Vel 40mg BID (D 1-7, 15-21), Cap 1000mg/m2 BID (D 1-7, 15-21), and Ox 85mg/m2 (D 1 and 15). Clinical trial information: NCT01233505. [Table: see text]

Phase I study of intraperitoneal MHC unrestricted adoptive cell therapy with TALL-104 cells in patients with peritoneal carcinosis

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3054-3054 ◽  
Author(s):  
C. Bengala ◽  
V. Rasini ◽  
R. Sternieri ◽  
M. Dominici ◽  
A. Andreotti ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Study ◽  
Mononuclear Cells ◽  
Adoptive Cell Therapy ◽  
Metastatic Breast ◽  
K562 Cells ◽  
Fold Increase ◽  
Breast Cancer Patients ◽  
Peritoneal Carcinosis ◽  
Dose Levels

3054 Background: TALL-104 is an irradiated human leukemic T cell line (CD3+, CD4- CD8+, CD56+, CD16-) grown in IL-2- containing medium, that has the ability to kill tumor cells in preclinical models in a MHC unrestricted way. A phase I trial in metastatic breast cancer patients, has shown that multiple i.v. infusions (infs) of TALL-104 cells can be given safely. In order to optimise the tumor:effector cell ratio, we have designed a phase I study of intraperitoneal infs of γ-irradiated TALL-104 cells. Methods: Patients (pts) with peritoneal carcinosis from ovarian or gastrointestinal tumors not responding to at least 2 lines of chemotherapy were eligible for study entry. The treatment included 5 i.p. infs (day 1, 3, 5, 15, 30) and the study aimed to test three cell dose levels: 1 x 108, 5 x 108, 2.5 x 109. End points of the study were: safety, kinetic of TALL-104 cells on ascites (if present) and peripheral blood (PB) by PCR, levels of cytokines (TGF-β, GM-CSF, IL-2, IL-4, IL-10, IFN-γ, TNF-a and -β, HGF, sIL-2R, sICAM-1) on ascites and serum, and cytotoxicity of autologous PB mononuclear cells (MNC) against K562 cells. Results: So far 10 pts have been treated: 6 with GI and 4 with ovarian cancer; 7 patients had ascites. Five pts have been treated at the 1st and 5 pts at the 2nd dose level. No treatment-related adverse events were observed. TALL-104 cells were detected in ascites (100 % of the pts) and PB (43 % of the pts) up to 48 hrs after the infs. Cytotoxicity of MNC showed a mean 5-fold increase at day 3 through 7 and it was still evident at day 30 in both dose levels. Cytokine levels are available for the first 5 pts. In one pt 18-fold increase of TNF-a was observed in ascites after the first infusion with a peak of 40-fold at day 15. sIL-2R and sICAM-1 showed both a mean 1.2-fold and 1.5-fold increase in serum in ascites respectively up to day 45. TGF-β1 level increased in average 3.3-fold in serum and 1.5-fold in ascites during the same observation period. HGF showed a mean 1.2-fold increase both in serum and ascites. Conclusions: These preliminary results show that the i.p. infusion of TALL-104 is safe. Moreover, the increased autologous cell-mediated cytotoxicity and the levels of soluble cytokines after i.p. infs indicate that TALL-104 cells may elicit potential antitumor activity. No significant financial relationships to disclose.

Phase I dose escalation study of CVM-1118, a novel anti-vascular mimicry agent, in patients with advanced cancers.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 2580-2580
Author(s):  
Anthony W. Tolcher ◽  
Wu-Chou Su ◽  
Nehal Lakhani ◽  
John Gutheil ◽  
Teresa J. Melink ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
Clinical Benefit ◽  
Drug Exposure ◽  
Network Formation ◽  
Oral Absorption ◽  
Malignant Tumors ◽  
Vasculogenic Mimicry ◽  
Tumor Xenograft ◽  
Dose Levels

2580 Background: CVM-1118 is an oral NCE that demonstrated potent anti-tumor effects in several tumor xenograft models, via multiple MOAs including induction of cancer cell cycle arrest and apoptosis, and reducing vasculogenic mimicry (VM) network formation in cancer cells, providing a promising therapeutic means in the treatment of malignant tumors that have metastatic potential. Methods: Patients with advanced tumors are being enrolled into 2 ongoing open-label Phase I dose escalation studies in both US (CVM-001) and Taiwan (CVM-002) to evaluate ethnic differences in drug responses. CVM-1118 capsules are administrated orally QD/BID in a 28-day cycle for 4 cycles. The primary objectives are to evaluate the safety, tolerability and pharmacokinetics (PK) and establish the Recommended Phase 2 Dose (RP2D). The secondary objective is to evaluate the therapeutic response after receiving treatment. Beyond 4 cycles, patients showing clinical benefit with CVM-1118 may enter extension cohort to continue the treatment. Results: To date, 28 pts (16 M/12 F)received CVM-1118 across 6 dose levels (50 to 800 mg daily). Median number of days was 52 (range 2 to 135). For CVM-001, 2 DLTs (grade 5 dehydration and grade 3 fatigue) were reported at cohort 6 (800 mg/daily) and the MTD is currently under evaluation. For CVM-002, 3 cohorts (100 to 400 mg/daily) have been completed without DLT. Enrolment to cohort 5 (600 mg/daily) is in progress. From both studies, the most common drug-related AEs included manageable diarrhea, nausea, and vomiting. Rapid oral absorption was observed with Tmax < 2 hr. Bioconversion to active metabolite, CVM-1125, occurred rapidly and the drug exposure increased with increasing dose levels. However, patients in US study showed higher drug exposure than those in Taiwan study. Two patients at 200 mg/daily cohort in Taiwan completing 4-cycle treatment and showing stable disease continued into extension cohort with higher dose. Conclusions: In this ongoing study, Asian patients in Taiwan appear to have better tolerance for CVM-1118 than those in US, likely due to lower drug exposure at same dose level, and some patients have experienced clinical benefit. Clinical trial information: NCT02507544; NCT02703298.

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