Addition of Oxaliplatin to Continuous Fluorouracil, l-Folinic Acid, and Concomitant Radiotherapy in Rectal Cancer: The Lyon R 97-03 Phase I Trial

2001 ◽  
Vol 19 (9) ◽  
pp. 2433-2438 ◽  
Author(s):  
Gilles Freyer ◽  
Nadine Bossard ◽  
Pascale Romestaing ◽  
Françoise Mornex ◽  
Olivier Chapet ◽  
...  
Keyword(s):  
Rectal Cancer ◽  
Phase I ◽  
Folinic Acid ◽  
Dose Level ◽  
Dose Escalation ◽  
Local Treatment ◽  
Rectal Adenocarcinoma ◽  
Severe Diarrhea ◽  
Phase Ii Studies ◽  
Level 1

PURPOSE: Oxaliplatin could increase the efficacy of fluorouracil (5-FU)/folinic acid chemoradiotherapy in rectal cancer. We tested three dose levels to identify a feasible oxaliplatin dose for combination therapy. PATIENTS AND METHODS: Between February 1998 and April 2000, we included 17 rectal adenocarcinoma patients in a single-center phase I study. Patients had T4 rectal carcinoma, T1-T3 disease with colostomy refusal, or potentially operable T2/T3 M1 requiring local treatment. Pelvic radiotherapy was 45 Gy over 5 weeks, 1.8 Gy/fraction, with concomitant chemotherapy weeks 1 and 5. Chemotherapy was oxaliplatin 80, 100, or 130 mg/m2 2-hour infusion on day 1 followed by l-folinic acid 100 mg/m2/d intravenous bolus, and 5-FU 350 mg/m2/d continuous infusion on days 1 to 5 (FolfoR1). Six patients refusing surgery received additional contact radiotherapy +/− brachytherapy. Dose escalation proceeded if less than two of six patients had dose-limiting toxicity (DLT) at a given dose-level. RESULTS: All except two patients completed treatment; patients at level 1 (prolonged grade 1 thrombocytopenia) and level 3 (prolonged cold-related dysesthesia) had no second chemotherapy course. Median follow-up is 14 months (range, 2 to 28 months). One elderly patient at dose level 1 had DLT asthenia, severe diarrhea and vomiting, and more than 10% weight loss. There were no other DLTs and no severe rectitis or gastrointestinal toxicity. There were objective responses at all doses and no progressions. Eight patients underwent radical surgery after chemoradiotherapy. Two had complete pathologic responses. CONCLUSION: FolfoR1 seems feasible and effective. Dose escalation did not increase toxicity. Although the MTD was not reached in this study, we recommend oxaliplatin 130 mg/m2 for phase II studies because it is the dose determined from studies in metastatic patients with no toxicity when given concurrently with radiation.

Combination of 5FU-based chemoradiation with EGFR inhibitor cetuximab and effect on PCR rate in patients undergoing neoadjuvant treatment in advanced rectal cancer.

2014 ◽  
Vol 32 (3_suppl) ◽  
pp. 623-623 ◽  
Author(s):  
Robert Semrau ◽  
Martin Kocher ◽  
Daniel Vallbohmer ◽  
Arnulf Hoelscher
Keyword(s):  
Rectal Cancer ◽  
Phase I ◽  
Dose Level ◽  
Combined Treatment ◽  
Neoadjuvant Treatment ◽  
Advanced Rectal Cancer ◽  
R0 Resection ◽  
Egfr Inhibitor ◽  
Level 1 ◽  
Level 2

623 Background: Neoadjuvant chemoradiation is a standard treatment for advanced rectal cancer patients. Here, we investigate whether treatment combined with the EGFR inhibitor cetuximab could enhance prognosis. Safety and efficacy (pathohistological regression rate, pCR) of chemoradiation in combination with cetuximab were evaluated. Methods: In a single-center phase I/II study patients with adenocarcinoma of the rectum (up to 16 cm above the anal verge) in stage cT3-4, cN0-1, were treated with cetuximab (weekly 250mg/m2, loading dose 400mg/m2) combined with radiotherapy (50,4Gy in 28 fractions) and 5-FU. Maximal tolerated dose of 5FU in combination with cetuximab and radiotherapy was determined in a phase I part (3+3 design; dose level 1: 750 mg/m2 5FU days 1-5 and 29-33; dose level 2: 1000 mg/m2 5FU days 1-5 and 29-33. Surgery was performed between 4 to 6 weeks after combined treatment. pCR rate of tumor cells was determined after surgery. Results: 20 patients were included into the trial, 19 patients received treatment: In the phase I part 2 out of 6 patients in level 2 experienced dose limiting toxicities (thrombocytopenia and diarrhea grade 3). Therefore, dose level 1 was considered safe for further enrollment. All 19 patients received the complete course of radiotherapy (50,4Gy). 15 patients received the complete cetuximab schedule, one patient discontinued after an allergic reaction at the first infusion, 3 patients missed 1 cycle of cetuximab in week 3 or 6. 18 patients continued to surgery. Sphincter preservation surgery was performed in 12 patients (63.2%), R0-resection rate was 100%. pCR grade IV (pCR) was documented in 1 patient (5,5%), grade III in 4 patients and grade I and II in 13 patients. So far no local recurrences occurred, 4 patients died (3 patients due to metastatic disease progression). Conclusions: The MTD of 5FU in combination with radiotherapy and cetuximab was 750mg/m2. Treatment was well tolerated and did not alter surgical management. However, pCR-rate was not elevated compared to standard 5FU-based preoperative chemoradiation. Whether the addition of cetuximab improves prognosis in this group of patient remains unclear. Clinical trial information: 2005-004139-23.

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]

A phase I trial of the oral hedgehog inhibitor taladegib (LY2940680) in combination with weekly paclitaxel in patients with advanced, solid tumours.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 2594-2594
Author(s):  
Rosalind Margaret Glasspool ◽  
Sarah Patricia Blagden ◽  
Michelle Lockley ◽  
James Paul ◽  
Carol Hopkins ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Dose Escalation ◽  
Single Agent ◽  
Primary Objective ◽  
Solid Tumours ◽  
Muscle Cramp ◽  
Weekly Paclitaxel ◽  
Level 1 ◽  
Level 2

2594 Background: Aberrant Hedgehog (Hh) signaling is implicated in carcinogenesis and is associated with poor prognosis in multiple tumours types. Hh inhibitors increase sensitivity to paclitaxel in taxane-resistant cell lines. Taladegib is an orally bioavailable, potent inhibitor of Smoothened, a key Hh pathway component, with activity in basal cell carcinoma. The single agent recommended dose is 400mg od. We present the dose escalation phase of a phase I study of weekly paclitaxel with oral taladegib. Methods: Primary objective: determine the dose limiting toxicity (DLT) and maximum tolerated dose (MTD) of taladegib on a continuous oral daily dosing regimen in combination with paclitaxel (80mg/m2, iv, day 1, 8 and 15 q 28) in patients with advanced solid cancers. Secondary objectives: assess the safety and tolerability, determine the recommended phase II dose (RP2D), and evaluate the pharmacokinetics of taladegib and paclitaxel. Exploratory objective: assess preliminary efficacy. A standard 3 + 3 dose escalation design was used. All patients received up to 6 cycles of paclitaxel. In addition, successive cohorts received continuous oral taladegib continued until progression or unacceptable toxicity as follows: dose level 1: 100mg od; 2: 200mg od; 3: 400mg od. Results: No DLTs were seen at dose level 1 or in the first 3 patients at dose level 2. 3 DLTs of grade 2 neuropathy were seen at dose level 3 (400mg taladegib); therefore, dose level 2 was expanded to 6 patients. No DLT was seen in the fourth patient and 2 additional patients have started treatment. After the DLT period 2 patients developed G2 and 4 developed G1 neuropathy. Other non DLT, drug-related G3 toxicities: uncomplicated neutropenia x2, muscle cramp x1 and fatigue x1. To date, 3 patients have had partial responses. Conclusions: The combination of daily oral taladegib and weekly paclitaxel is feasible. DLT of G2 neuropathy was seen at 400mg. Promising activity has been seen in solid tumours. A dose expansion cohort is due to commence in high grade ovarian carcinoma. ISRCTN No:ISRCTN15903698 Eudract Ref:2014-004695-37 Funded by Cancer Research UK C8361/A18775 and Ignyta. Sponsored by NHS Greater Glasgow and Clyde. Clinical trial information: ISRCTN15903698.

Phase I/II Study of Bortezomib in Combination with Liposomal Doxorubicin and Melphalan in Relapsed or Refractory Multiple Myeloma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5182-5182 ◽  
Author(s):  
Ajai Chari ◽  
Lawrence Kaplan ◽  
Charles Linker ◽  
Lloyd E. Damon ◽  
Willis H. Navarro ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Dose Escalation ◽  
Progressive Disease ◽  
Liposomal Doxorubicin ◽  
Maximum Tolerated Dose ◽  
Dose Escalation Study ◽  
Heavily Pretreated ◽  
Level 1 ◽  
Grade 3

Abstract Phase I/II studies using either liposomal doxorubicin (D) or oral melphalan (M) in combination with the proteasome inhibitor bortezomib (V) have found favorable efficacy and tolerance in patients with relapsed and refractory MM. Since these drugs have different mechanisms of action and toxicity profiles, we initiated a phase I/II study to examine the safety and efficacy of combining all three agents (DMV) in relapsed or refractory myeloma. Study Aims: Starting at 25–50% of the doses used in the two drug combination studies, the objective of this dose escalation study was to evaluate the safety/tolerability of DMV until the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) could be identified. Efficacy was also evaluated. Methods: Patients with relapsed/refractory MM and progressive disease requiring treatment were enrolled in the study. Dose level 1 consisted of D 10 mg/m2 and M 5 mg/m2 given IV on day 1 with V given by IV push on days 1, 4, 8, and 11. Cycles were repeated every 28 days up to a maximum of 6 cycles. Dose levels of D, M, V (mg/m2) in the subsequent three cohorts were (10, 10, 0.7), (20, 10, 0.7), and (20, 10, 1.0) respectively. Once the MTD has been identified, an additional 17 patients will be enrolled at this dose level in the phase II portion of the study. Results: 5 patients (2 males, median age 65, range 33–79) have been enrolled in the study thus far. The myeloma subtypes include 2 IgG, 1 IgA, and 2 with light chains only. In this heavily pretreated population (range 2–7 prior therapies), 4 patients received prior autologous stem cell transplantation, 2 had a prior nonmyeloablative allogenic transplant, 4 prior VAD, 1 prior bortezomib, 2 prior oral melphalan, 3 prior thalidomide, 2 prior CC-5013, and 2 prior spinal radiation. The first dose cohort has been completed without any DLT. One patient had 3 days of Grade 3 neutropenia. All other toxicities were Grade 1–2 including asthenia, vomiting, thrombocytopenia, and headache. Of note, a patient with baseline Grade 2 peripheral neuropathy and on hemodialysis remained stable. A patient with Grade 2 chronic graft versus host disease also remained stable. Four patients have been enrolled at dose level one. One patient, who had progressive disease after an autologous and a nonmyeloablative allogenic transplant as well as CC5013, had a near CR (IFE+) after the second cycle of DMV. Two patients have had stable disease. One had disease progression after one cycle and subsequently died. The patient on dose level two is too early to evaluate. Conclusion: Thus far, DMV appears to be well tolerated and no DLT has been observed even in elderly patients with significant comorbidities. The finding of a near CR and SD at only dose level 1 is encouraging particularly since the patients were significantly pretreated. Dose escalation continues to determine the MTD.

Vincristine Sulfate Liposomes Injection (VSLI, Marqibo): Interim Results From a Phase I Study in Children and Adolescents with Refractory Cancer

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1497-1497
Author(s):  
Nirali N Shah ◽  
Melinda Merchant ◽  
Diane Cole ◽  
Kelly Richards ◽  
Cindy Delbrook ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Level ◽  
Dose Escalation ◽  
Pediatric Patients ◽  
Pharmacokinetic Analysis ◽  
Motor Neuropathy ◽  
Vincristine Sulfate ◽  
Level 1 ◽  
Dose Levels

Abstract Abstract 1497 Background: Vincristine is active in many pediatric cancers, but cumulative neuromuscular toxicity is often dose limiting and requires a maximum dose cap. Liposomal carriers are capable of increasing the therapeutic index of anticancer agents by altering pharmacokinetic behavior. Vincristine sulfate liposomes injection (VSLI, Marqibo®) is a novel preparation of standard vincristine encapsulated in sphingomyelin/cholesterol liposomes. Clinical trials have demonstrated safety, tolerability and activity in adults with leukemias, lymphomas and solid tumors. Pediatric experience with VSLI is limited. Design: This single center Phase I dose-escalation study is designed to determine the maximum tolerated dose (MTD) and to assess safety, pharmacokinetics and activity of VSLI in pediatric patients with relapsed/refractory cancer. Patients with active central nervous system disease or ≥grade 2 sensory or motor neuropathy are excluded. Dose escalation is per a standard 3 + 3 Phase I trial design with enrollment following a rolling 6 strategy. VSLI is administered IV over 60-minutes every 7 days (± 3 days) for 4 consecutive weeks for a 28-day treatment cycle (4 doses/cycle). Cycles may be delayed by up to 1 week for toxicity. Two dose levels have been tested to date: 1.75 mg/m2 and 2.25 mg/m2(adult MTD). No individual dose cap is employed. A validated HPLC tandem mass spectrometry assay was used to quantitate total (liposomal encapsulated and non-encapsulated) vincristine. Results: 9 patients have been treated (Table): 6 with acute lymphoblastic leukemia (ALL) and 3 with solid tumors. All patients were heavily pre-treated and 2 had prior stem cell transplants. 6 of 9 completed at least 1 cycle of therapy, with 1 each removed early for alternative therapy, complications of ALL, or dose-limiting toxicity (DLT). Most treatment-related adverse events were reversible grade 1 and 2 severity including hepatic transaminase elevation, parasthesia, low white blood cell count, neutropenia and fatigue. 2 patients evaluable for hematologic toxicity developed grade 4 neutropenia that spontaneously and rapidly resolved. No DLT occurred on dose level 1. Grade 4 aspartate aminotransferase elevation was observed in one patient at the second dose level and this dose level is being expanded. 1 patient treated at dose level 1 had dose de-escalation starting with Cycle 2 Dose 3 due to neuropathy. No patient was taken off study due to neurotoxicity. 7 of 9 patients received a VSLI dose that exceeded the 2 mg dose limit set for standard vincristine. 6 patients were evaluable for response: 1 had a complete remission (CR) (minimal residual disease negative by flow cytometry); 3 had stable disease (SD); and 2 had progressive disease (PD). First-dose pharmacokinetic analysis revealed wide interpatient variation (Table). The median (range) maximum concentrations (Cmax) of total vincristine (ng/ml) were 1,485 (845-2,120) and 2,450 (1,690-3,690) at dose levels 1 and 2 respectively. The median plasma half-life (T½) was 8.5 and 13.5 hours at dose levels 1 and 2 respectively (range 1.8 to 40.4 hours). Conclusions: VSLI appears to be safe, tolerable and demonstrates preliminary activity in pediatric patients with refractory ALL and solid tumors. The toxicity spectrum appears to be similar in children and adults. Clearance of total vincristine in our study is approximately 100-fold lower in comparison to administration of standard vincristine. VSLI allows for intensification of vincristine therapy in children with cancer. Accrual to the Phase I component at the adult recommended dose is ongoing and an expanded Phase II cohort in pediatric patients with ALL is planned. This study was sponsored by Talon Therapeutics and is supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. Disclosures: No relevant conflicts of interest to declare.

Phase I trial of vendetanib and oral etoposide for recurrent malignant gliomas

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e13016-e13016
Author(s):  
J. Herndon ◽  
J. Vredenburgh ◽  
D. Reardon ◽  
A. Desjardins ◽  
K. Peters ◽  
...  
Keyword(s):  
Growth Factor ◽  
Phase I ◽  
Malignant Glioma ◽  
Dose Level ◽  
Dose Escalation ◽  
Phase I Trial ◽  
Malignant Gliomas ◽  
Oral Etoposide ◽  
Level 1 ◽  
Grade 3

e13016 Background: Recurrent malignant gliomas have a poor prognosis, with a median survival of 6–15 months, with grade 4 glioblastomas more aggressive than grade 3 anaplastic astrocytomas or oligodendrogliomas. Vascular endothelial growth factor (VEGF) and epidermal growth factor (EGF) are critically important in glioma biology. Vandetanib is a multi-kinase inhibitor, predominantly of VEGF and EGF. We report a phase I trial of vandetanib in combination with oral etoposide for recurrent malignant glioma. Methods: Patients with histologically documented recurrent grade 3 or grade 4 malignant glioma were eligible. Patients were treated with daily oral vandetanib and oral etoposide. The trial design was a modified 3 + 3 Phase I design, with the dose levels outlined below. Results: Eighteen patients have been accrued. There was more hematologic toxicity than expected, with 3/6 of the patients enrolled at dose level 1 developing grade 4 neutropenia. There were no DLT's at the -1 dose level. The protocol was amended to decrease the dose of etoposide to 50 mg daily for 21 days, then 7 days off and dose escalation of vandetanib started again at 100 mg daily. Six patients had no dose limiting toxicity at the new dose level 1 of vandetanib 100 mg daily and etoposide 50 mg daily. Dose escalation continues. There has been clinical activity, with patients remaining stable on study for multiple cycles. Conclusions: Vandetanib and oral etoposide appear to interact to produce more marrow toxicity than expected. A phase II trial is planned when the MTD of vandetanib with reduced dose etoposide is determined. [Table: see text] No significant financial relationships to disclose.

scholarly journals Phase I Radiation Dose-Escalation Study to Investigate the Dose-Limiting Toxicity of Concurrent Intra-Arterial Chemotherapy for Unresectable Hepatocellular Carcinoma

Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1612
Author(s):  
Yeona Cho ◽  
Jun Won Kim ◽  
Ja Kyung Kim ◽  
Kwan Sik Lee ◽  
Jung Il Lee ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Radiation Dose ◽  
Phase I ◽  
Dose Level ◽  
Dose Escalation ◽  
Level 3 ◽  
Level 1 ◽  
Grade 3 ◽  
Dose Limiting Toxicity

Concurrent intra-arterial chemotherapy and radiotherapy (iA-CCRT) can increase the response rate in hepatocellular carcinoma (HCC), but may cause a higher toxicity. We conducted this Phase I study to investigate the dose-limiting toxicity of iA-CCRT for HCC. In total, 52.5 Gy in 25 fractions was prescribed as planning target volume (PTV) 1 at dose level 1. The dose escalation was 0.2 Gy per fraction and up to 2.5 Gy, with 62.5 Gy at level 3. Concurrent intra-arterial 5-fluorouracil was administered during the first and fifth weeks of radiotherapy (RT). Toxicities were graded using the Common Toxicity Criteria for Adverse Events, version 4.0. Results: Seventeen patients with HCC were analyzed: four at dose level 1, 6 at level 2, and 7 at level 3. The mean irradiated dose administered to the uninvolved liver at each dose level was 21.3, 21.6, and 18.2 Gy, respectively. There was no grade ≥3 gastrointestinal toxicity; two patients experienced grade 3 hyperbilirubinemia. All patients had Child-Pugh class A disease, but 3 patients developed class B disease after iA-CCRT. During a median follow-up of 13 months, the median progression-free survival (PFS) and overall survival (OS) were 10 and 22 months, respectively. Patients treated at dose level 3 showed improved PFS and OS. Conclusions: Radiation dose escalation of iA-CCRT did not cause any significant toxicities in patients with advanced HCC. Further large-scale studies with long-term follow-up are needed to determine the efficacy and feasibility of higher doses of iA-CCRT.

A phase I trial of plinabulin in combination with nivolumab and ipilimumab in patients with relapsed small cell lung cancer (SCLC): Big Ten Cancer Research Consortium (BTCRC-LUN17-127) study.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 8570-8570
Author(s):  
Jyoti Malhotra ◽  
Nasser H. Hanna ◽  
Alberto Chiappori ◽  
Lawrence Eric Feldman ◽  
Naomi Fujioka ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Dose Escalation ◽  
Phase I Study ◽  
Infusion Reaction ◽  
Phase 2 ◽  
Vascular Disrupting Agent ◽  
Level 1 ◽  
Grade 3 ◽  
Level 2

8570 Background: Plinabulin (BPI-2358) is a vascular disrupting agent with immune-enhancing function by inducing dendritic cell maturation and decreasing regulatory T cells. Preclinical studies report that plinabulin potentiates the cytotoxicity of dual checkpoint inhibition (CPI) with nivolumab and ipilimumab. Plinabulin may also reduce immune-related AEs from CPI through its phosphodiesterase-4 (PDE4) inhibitory activity which is associated with anti-inflammatory effects. We report initial results from a Phase I study assessing plinabulin in combination with nivolumab and ipilimumab. Methods: In this dose-escalation phase I study, patients with extensive-stage SCLC who had progressed on or after prior platinum-based chemotherapy (±CPI) were enrolled using a 3+3 design. The primary objective was to determine dose-limiting toxicities (DLT’s) and recommended Phase 2 dose (RP2D). Patients received nivolumab (1 mg/kg), ipilimumab (3 mg/kg) and plinabulin (as per dose escalation schema) IV on day 1 of each 21 day cycles. After completion of 4 cycles, patients continued therapy with nivolumab (240 mg) and plinabulin every 2 weeks till progression or intolerable toxicity. Patients were evaluable for DLT if they received at least 2 cycles of therapy; DLT period was defined as the first 6 weeks from C1D1. Secondary endpoints were ORR, PFS and frequency of irAEs. Correlative analysis included inflammatory biomarkers: hsCRP, ESR, SAA and haptoglobin. Results: Between 9/2018 and 11/2020, 17 patients were enrolled (1 patient withdrew consent before treatment, 16 were evaluable for safety). Median age was 59 years (range 43 to 78); 9 patients were male and 10 had received prior CPI. Eight patients were treated at dose-level 1 of plinabulin (20 mg/m2) and 8 patients at 30 mg/m2 of plinabulin (level 2); dose-level 2 was determined to be RP2D. There were 2 DLTs; 1 at dose-level 1 (grade 3 altered mental status lasting < 24 hours) and 1 at dose-level 2 (grade 3 infusion reaction). The most common treatment-related AEs (all grades) were nausea (10; 63%), infusion reaction (8; 50%), vomiting (7; 44%), diarrhea (7; 44%) and fatigue (6, 32%). Seven patients (44%) had at least one grade 3 or higher treatment-related AE; there were no treatment-related deaths. Two patients (13%) had grade 3 or higher irAE requiring steroids (1 colitis, 1 transaminitis); both at dose-level 1. At data cutoff (12/30/20), there were 3 PRs in CPI naïve patients (3/6; 50%) and 2 PRs in evaluable CPI-resistant patients (2/7; 29%). In the two CPI-resistant patients with confirmed response, the tumor reduction was 68% and 52%. Conclusions: Plinabulin in combination with nivolumab and ipilimumab was safe and well tolerated. A phase 2 study in CPI-experienced patients with relapsed SCLC is planned to confirm the preliminary signals of clinical activity and reduced immune toxicity. Clinical trial information: NCT03575793.

A Phase I Study of GTI-2040, an Antisense to Ribonucleotide Reductase (RNR) in Combination with High-Dose Cytarabine (HiDAC) in Relapsed or Refractory Acute Myeloid Leukemia (AML): Pharmacokinetics (PK), Pharmacodynamic (PD) and Clinical Results.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2790-2790 ◽  
Author(s):  
Rebecca B. Klisovic ◽  
W. Blum ◽  
X. Wei ◽  
S. Liu ◽  
C. Kefauver ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Dose Escalation ◽  
Intermediate Risk ◽  
Refractory Disease ◽  
Phase Ii Trials ◽  
Disease Response ◽  
Level 1 ◽  
Grade 3 ◽  
Dna Incorporation

Abstract GTI-2040 is a 20-mer antisense to the R2 component of RNR mRNA. RNR is required for the conversion of ribonucleotides to deoxyribonucleotides, a crucial step during DNA synthesis and repair. Cytarabine (AraC) is a cytotoxic agent that is converted into AraC triphosphate (Ara-CTP) and is the backbone of several regimens in AML. Ara-CTP competes with deoxycytidine for DNA incorporation. We hypothesize that RNR downregulation by GTI-2040 results in decrease of levels of deoxycytidine thereby leading to a preferential DNA incorporation of ARA-CTP and increase in its cytotoxic activity. To test this hypothesis we undertook a CTEP-sponsored Phase I dose-escalation study of GTI-2040 plus HiDAC in patients (pts) with relapsed or refractory AML. Pts were stratified in 2 cohorts according to age. Cohort I (18–59 yrs) received escalating doses of GTI-2040 (dose level 1: 3.5 mg/m2/d) by continuous IV infusion (CIVI) on d 1–6 combined with escalating doses of cytarabine IV over 2 hrs q12 hrs on d 2, 4, and 6 (dose level 1: 2500 mg/m2/dose). Cohort II (≥60 yrs) received GTI CIVI on d 1–6 and cytarabine IV over 4 hrs on d 2 to 6 (dose level 1: 1500 mg/m2/d). To date, 30 pts were enrolled. Pts received median of 1 prior regimen (range 1–3). Cohort I included 8 pts with relapsed and 6 with refractory disease; 7 had intermediate risk cytogenetics (CyG) and 7 adverse CyG; 6 received prior HiDAC. Cohort II included 10 pts with relapsed and 6 with refractory disease; 8 pts had intermediate risk CyG and 8 high risk CyG; 5 pts received prior HiDAC. Toxicities were comparable to HiDAC therapy alone. Grade 3/4 non-hematologic toxicities included fatigue, fevers, anorexia, pneumonitis, and catheter related infections; a grade 3 reversible cerebellar toxicity (n=1) was observed at level 1/cohort I. An ELISA-based assay with a limit of quantification of 50 pMol was used to determine GTI2040 plasma and intracellular (IC) concentrations. Dose-dependent increase in plasma steady state concentration (Css) and area under the curve (AUC) of GTI2040 was observed in both cohorts, although higher AUC and longer t1/2 were demonstrated in the younger pts compared to the older ones. In cohort I, disease responses were seen at all dose levels Five of 14 pts achieved complete remission (CR) and one achieve incomplete CR (CRi; i.e., no marrow disease and incomplete blood count recovery). In cohort II, no disease response was observed. Median IC GTI2040 concentration in BM mononuclear cells at 120 hours following start of antisense infusion was higher in younger (i.e., 175 nM) than in older (i.e., 75 nM) pts. A median decrease in R2 protein levels of 50% (range 50–90%) detected by immunoblotting was noted in 5/9 and 5/10 pts in cohort I and II, respectively. In cohort I CR pts (n=4) had a median 50% decrease and non-responders (n=9) had a median 200% increase in R2 levels. In cohort II changes in R2 levels did not predict disease response. In summary, combination of GTI-2040/HiDAC is feasible. PK/PD studies demonstrate achievable plasma and IC levels of the antisense and target downregulation. Disease response was observed only with the dose/schedule administered to younger pts. Dose escalation in this group continues to establish a recommended dose for Phase II trials. [NCI U01 CA 76576-05].

A phase I/II trial of sorafenib (S) with bevacizumab (B) in metastatic renal cell cancer (mRCC) patients (Pts)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 3031-3031 ◽  
Author(s):  
J. A. Sosman ◽  
K. Flaherty ◽  
M. B. Atkins ◽  
I. Puzanov ◽  
D. F. McDermott ◽  
...  
Keyword(s):  
Growth Factor ◽  
Phase I ◽  
Dose Level ◽  
Phase Ii ◽  
Clear Cell ◽  
Cell Cancer ◽  
Growth Factor Receptor ◽  
Phase Ii Studies ◽  
Level 1 ◽  
Grade 3

3031 Background: In an effort to enhance the efficacy of vascular endothelial growth factor (VEGF) pathway blockade in mRCC we initiated a Phase I-II trial of combination S and B to block VEGFR signaling and VEGF binding, as well as, platelet derived growth factor receptor β (PDGFR) signaling. Methods: Pts with measurable (RECIST) mRCC, adequate organ function, and PS 0–1 were eligible for this trial. Cohorts of 6 pts were enrolled at 3 sites to define the MTD and DLT of the combination of S and B. The schedule was B IV q 14 days and S daily with cycles of 28 days. Response and toxicity were assessed at the end of 2 cycles. Dose levels began with S at 200mg BID and B at 5 mg/kg (level 1) with the hope to reach phase II doses of both agents (S at 400mg BID and B at 10mg/kg). The MTD or the phase II dose of each agent would then be administered to up to 45 pts with mRCC, clear cell histology, and prior nephrectomy. Results: A total of 18 patients have been enrolled to date, with 15 completing their first response evaluation. Pts were median age 61 years (46–74 range); M/F: 15/3; PS: 0/1= 12/6; 17 clear cell, 1 chromophobe, 11 prior nephrectomy; 4 with prior cytokine therapy. Two pts in level 1 experienced DLT with recurrent and intolerable (grade 3) hand-foot syndrome (HFS). An additional 6 patients were treated at dose level -1 (S at 200mmg QD and B at 3mg/kg) with no DLTs. Six more pts have been treated at dose level 1 with Vit B6 at 300mg/d in an attempt to minimize HFS. Toxicity data in this cohort is incomplete. Additional toxicities among the 18 pts included grade 3 hypertension (4), grade 3 proteinuria (2), and grade 2 stomatitis (3). Responses including 4 objective PRs, and 4 pts with 20–30% regression have been seen in the 14 evaluated pts. Only 2 patients have had disease progression. Conclusions: The phase II doses for this combination have not yet been established, but will likely be lower than the full phase II doses of the individual agents. The toxicities from HFS (primarily) and hypertension and stomatitis appear to be limiting. Even at the initial low doses of S and B, significant anti-tumor activity has been observed. The completion of this phase I trial will be reported. The phase II studies in mRCC are highly anticipated. Support by phase I contract UO-1 CA099177 [Table: see text]

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