scholarly journals Concomitant intraperitoneal and systemic chemotherapy for extensive peritoneal metastases of colorectal origin: protocol of the multicentre, open-label, phase I, dose-escalation INTERACT trial

BMJ Open ◽  
2019 ◽  
Vol 9 (12) ◽  
pp. e034508 ◽  
Author(s):  
Nadine Leonie de Boer ◽  
Alexandra R M Brandt-Kerkhof ◽  
Eva V E Madsen ◽  
Marjolein Diepeveen ◽  
Esther van Meerten ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Phase I ◽  
Dose Escalation ◽  
Intraperitoneal Chemotherapy ◽  
Systemic Chemotherapy ◽  
Standard Of Care ◽  
Peritoneal Metastases ◽  
Access Port ◽  
Abdominal Disease ◽  
Colorectal Origin

IntroductionCytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) has become standard of care for patients with peritoneal metastases of colorectal origin with a low/moderate abdominal disease load. In case of a peritoneal cancer index (PCI) score >20, CRS-HIPEC is not considered to be beneficial. Patients with a PCI >20 are currently offered palliative systemic chemotherapy. Previous studies have shown that systemic chemotherapy is less effective against peritoneal metastases than it is against haematogenous spread of colorectal cancer. It is suggested that patients with peritoneal metastases may benefit from the addition of intraperitoneal chemotherapy to systemic chemotherapy. Aim of this study is to establish the maximum tolerated dose of intraperitoneal irinotecan, added to standard of care systemic therapy for colorectal cancer. Secondary endpoints are to determine the safety and feasibility of this treatment and to establish the pharmacokinetic profile of intraperitoneally administered irinotecan.Methods and analysisThis phase I, ‘3+3’ dose-escalation, study is performed in two Dutch tertiary referral centres. The study population consists of adult patients with extensive peritoneal metastases of colorectal origin who have a good performance status and no extra-abdominal metastases. According to standard work-up for CRS-HIPEC, patients will undergo a diagnostic laparoscopy to score the PCI. In case of a PCI >20, a peritoneal access port will be placed in the abdomen of the patient. Through this port we will administer intraperitoneal irinotecan, in combination with standard systemic treatment consisting of 5-fluorouracil/leucovorin with oxaliplatin and the targeted agent bevacizumab. Therapy consists of a maximum of 12 cycles 2-weekly.Ethics and disseminationThis study protocol is approved by a research medical ethics committee (Rotterdam, Netherlands) and the Dutch Competent Authority (CCMO, The Hague, Netherlands). The results of this trial will be submitted for publication in a peer-reviewed scientific journal.Trail registration numberNL6988 and NL2018-000479-33; Pre-results.

Phase I study of ABT-751 in combination with CAPIRI (capecitabine and irinotecan) and bevacizumab in patients with advanced colorectal cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 13553-13553
Author(s):  
W. A. Messersmith ◽  
M. A. Rudek ◽  
D. Laheru ◽  
M. Zhao ◽  
P. He ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Combination Therapy ◽  
Phase I ◽  
Dose Level ◽  
Dose Escalation ◽  
Advanced Colorectal Cancer ◽  
Standard Of Care ◽  
Maximum Tolerated Dose ◽  
Total Daily Dose ◽  
Dose Escalation Study

13553 Background: ABT-751 (A) is an orally (PO) bioavailable sulfonamide with antimitotic properties. We are performing a non-randomized phase I/II dose-escalation study of A in combination with capecitabine (C), irinotecan (I) and bevacizumab (B) to define the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and pharmacokinetics (PK) in patients with advanced colorectal cancer (1st or 2nd line). Methods: Patients are treated with A QD for 7d (lead-in) and then begin 21-d cycles of treatment with A (QD) and C (BID) d1–14 PO, I d1 IV, and B d1 IV. Dose escalation started at dose level (DL) 1 at A 150 mg, I 200 mg/m2, and C 1600 mg/m2 (total daily dose) and escalated to full dose CAPIRI (I 250 mg/m2, and C 2000 mg/m2) for DL2. B was then added as standard of care at 7.5 mg/kg for DL2b (and later, DL1b). Blood samples were collected for pharmacogenomics (PG), pharmacodynamics (PD), steady-state PK of A and A metabolites when administered alone or in combination with C, I, and B, and PK of I and I metabolites. Serial dynamic contrast MRI’s, before and after the ABT-751 monotherapy lead-in period, are being performed in a subset of subjects. Results: Eight patients have been treated at dose levels 1 (3), 2 (2), and 2b (3). One patient on DL2 experienced g3 transaminitis and another on DL2b had F&N which were dose-limiting. Dose level 1 is being expanded to 6 patients, now with B (DL1b). Other g3/4 toxicities have included g4 neutropenia (1 subject DL2, 1 DL2b). The formation of A glucuronide appears decreased during combination therapy (see table). I PK, PD, and PG samples were collected and analysis is pending. Of 8 subjects, there have been 4 PD and 4 SD after 2 cycles. Conclusions: The combination therapy of A 150 mg and 20% dose-reduced CAPIRI appears well-tolerated. Patient accrual continues at DL1b. [Table: see text] No significant financial relationships to disclose.

A phase I dose-escalation trial of intraperitoneal oxaliplatin with systemic capecitabine and bevacizumab following cytoreduction in patients with peritoneal carcinomatosis from appendiceal or colorectal cancer.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 746-746
Author(s):  
Aabha Oza ◽  
Patrick Grierson ◽  
Sean Glasgow ◽  
Katrina Pedersen ◽  
Stephen Barman ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Abdominal Pain ◽  
Phase I ◽  
Peritoneal Carcinomatosis ◽  
Dose Escalation ◽  
Systemic Therapy ◽  
Systemic Chemotherapy ◽  
Repeated Treatment ◽  
Dose Escalation Study ◽  
Grade 3

746 Background: Peritoneal carcinomatosis (PC) is the intraperitoneal spread of cancer. Optimal treatment for PC is controversial. Systemic chemotherapy offers limited benefit (Franko, 2011). Intraperitoneal (IP) chemotherapy following cytoreductive surgery (CRS) improves outcomes (Verwaal, 2008). Oxaliplatin (Ox), capecitabine, and bevacizumab are standard agents for the treatment of metastatic colorectal cancer (CRC). Evidence suggests benefit of IP Ox at high doses. However, the optimal dose of IP Ox combined with standard systemic therapy is unclear. Methods: We conducted an IRB-approved phase I dose-escalation study of IP Ox D1 at 25mg/m2-100mg/m2, with systemic bevacizumab D1 at 5mg/kg, and capecitabine 850mg/m2 BID for 7 days (cycle = 14 days), in patients with PC from appendiceal or CRC after CRS. The primary aim was to determine the recommended phase II dose (RP2D)/maximum tolerated dose (MTD) for this regimen. Dose limiting toxicities (DLTs) were assessed during cycle 1. DLTs included grade 3 or 4 non-hematological toxicities, or grade 4 hematological toxicities. Results: 18 patients (12 females, median age 56) were enrolled on the study. No DLTs were observed during cycle 1 in the first 4 cohorts. One DLT (abdominal pain) was observed in cohort 5. Another patient in cohort 5 experienced grade 3 abdominal pain soon after cycle 2, thus limiting repeated treatment for this cohort. Other toxicities included fatigue (72%), nausea (61%), peripheral neuropathy (50%), constipation (50%), mucositis (39%) and dizziness (39%). See table below for average # of cycles per cohort and responses. Conclusions: IP Ox combined with capecitabine and bevacizumab is feasible. Our recommended dose for IP Ox is 85 mg/m2 with systemic therapy (cohort 4). An expansion cohort is underway for this dose level. Based on these data, further investigation of IP Ox with systemic chemotherapy for PC is warranted. Clinical trial information: NCT01061515. [Table: see text]

scholarly journals Cytoreductive Surgery Combined with Hyperthermic Intraperitoneal Chemotherapy for Peritoneal Metastasis from Colorectal Cancer

2020 ◽  
Vol 33 (06) ◽  
pp. 372-376
Author(s):  
Hideaki Yano
Keyword(s):  
Colorectal Cancer ◽  
Intraperitoneal Chemotherapy ◽  
Cytoreductive Surgery ◽  
Peritoneal Metastasis ◽  
Hyperthermic Intraperitoneal Chemotherapy ◽  
Peritoneal Cancer Index ◽  
Systemic Disease ◽  
Good Reason ◽  
Standard Of Care ◽  
Peritoneal Cancer

AbstractPeritoneal metastasis from colorectal cancer (PM-CRC) is used to be considered a systemic and fatal condition; however, it has been growingly accepted that PM-CRC can still be local disease rather than systemic disease as analogous to liver or lung metastasis.Cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) is now considered an optimal treatment for PM-CRC with accumulating evidence. There is a good reason that CRS + HIPEC, widely accepted as a standard of care for pseudomyxoma peritonei (PMP), could be a viable option for PM-CRC given a similarity between PM-CRC and PMP.Recent years have also seen that modern systemic chemotherapy with or without molecular targeted agents can be effective for PM-CRC. It is possible that neoadjuvant or adjuvant chemotherapy combined with CRS + HIPEC could further improve outcomes.Patient selection, utilizing modern images and increasingly laparoscopy, is crucial. Particularly, diagnostic laparoscopy is likely to play a significant role in predicting the likelihood of achieving complete cytoreduction and assessing the peritoneal cancer index score.

scholarly journals Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for synchronous liver and peritoneal metastases from colorectal cancer: where is the limit?

HPB ◽  
2021 ◽  
Vol 23 ◽  
pp. S779
Author(s):  
L. Carrion-Alvarez ◽  
J.A. Martinez-Piñeiro-Muñoz ◽  
I. Manzanedo-Romero ◽  
V. Antolin-Sanchez ◽  
P. Haro-Preston ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Intraperitoneal Chemotherapy ◽  
Cytoreductive Surgery ◽  
Hyperthermic Intraperitoneal Chemotherapy ◽  
Peritoneal Metastases

scholarly journals A Safety Study of the Addition of Omacetaxine to the Standard-of-Care Induction Regimen of Cytarabine and Idarubicin in Newly-Diagnosed AML Patients

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5218-5218
Author(s):  
Sonia Christian ◽  
Kelley E. Kozma ◽  
Stephanie Barath ◽  
Ardaman Shergill ◽  
Damiano Rondelli ◽  
...  
Keyword(s):  
High Risk ◽  
Phase I ◽  
Dose Level ◽  
Dose Escalation ◽  
De Novo ◽  
Standard Of Care ◽  
Hematologic Toxicity ◽  
Newly Diagnosed ◽  
Induction Regimen ◽  
Dose Levels

Abstract Background: Omacetaxine mepesuccinate (OM) is a semi-synthetic form of Homoharringtonine (HH), a cephalotaxine alkaloid. OM induces cell apoptosis by inhibiting peptide bond formation during mRNA translation, with rapid loss of short-lived proteins, such as MCL-1, c-MYC, and Cyclin D1 (Lu, J Hematol Oncol. 2014, 7: 2). Notably, cytarabine synergizes with HH in causing apoptosis of leukemia cells in vitro. A phase III RCT in China of 620 patients with de novo AML demonstrated superior CR and 3-yr survival rates upon addition of HH to a standard 2-drug AML induction therapy ('7 + 3'; Jin, Lancet Oncol. 2013, 14:599). Thus, we hypothesized that OM, at an appropriate dose, would similarly enhance the efficacy of a 7 + 3 regimen. OM is FDA-approved for the treatment of TKI-resistant CML. The MTD of 1.25 mg/m2/d SQ for 14 days every 28 days, as determined in a phase I/II CML trial of OM (Quintás-Cardama, Cancer 2007, 109: 248), served as a basis for the dose escalation used in this study. Methods: The primary endpoint of this phase I safety trial was to determine the optimally safe and active dose (OD) of OM when added to a standard 7 + 3 induction regimen, cytarabine and idarubicin. OM was administered SQ q12h d1-7 with cytarabine (100mg/m2 CIV) d1-7 and idarubicin (12mg/m2 IV) d1-3. Four dose levels were tested, starting with OM 0.625 mg/m2 q12h (further dose levels: 1.25, 2.0, 3.0, and 4.2 mg/m2 q12h). All newly diagnosed, untreated de novo or secondary AML patients, aged 18-70y with ECOG PS of 0-3 were eligible for this study. Secondary endpoints included overall response rate (ORR) and overall and event free survival (OS, EFS). Hematologic toxicity (HT) was defined as incomplete hematologic recovery; ANC < 1.0 x 109/L or platelet count < 100 x 109/L present at d49, with the bone marrow documented to be free of leukemic infiltration. Dose escalation was based on the EffTox design (Biometrics 2004, 60:684), a Bayesian adaptive design which considers the trade-off between efficacy and toxicity in determining the OD for Phase II trials. Results: Twenty-two patients, median age 58 (range 25-69) years were enrolled from June 2015 to June 2018. 12 patients (54.5%) had adverse cytogenetics, 6 (27%) intermediate risk, 3 (13.7%) favorable risk and 1 patient's cytogenetic risk was unknown (fibrotic BM). Eight patients demonstrated disease evolution from myelodysplastic syndrome (MDS). Altogether 16 of the 22 patients (73%) were deemed high risk based on cytogenetics or MDS-AML evolution. The EffTox design was implemented until cohort 4 (3 mg/m2 q12h), where 2 of 3 patients experienced a grade 5 non-hematologic toxicity (NHT), resulting in a dose-limiting toxicity (DLT). Since no DLTs were observed in cohort 3, an additional 5 patients were thus enrolled at this dose level to ensure safety. The OD was determined to be the dose level used in cohort 3: OM 2 mg/m2. No HTs were observed in 21 of 22 patients, (one patient not evaluable). The most common non-hematologic treatment emergent adverse events (TEAEs) of any grade were fever (68%), nausea (64%), vomiting (55%), hyperglycemia (41%), diarrhea (41%), mucositis (36%), headache (36%), sinus tachycardia (32%), rash/dermatitis (32%), and abdominal pain (32%). The most prevalent non-hematologic grade 3/4 TEAEs were febrile neutropenia (23%), hypoxia (18%), hyperglycemia (18%), and dyspnea (18%). ORR (CR and CRi) was 45.5%. Median OS was 605 days and EFS was 100 days. Conclusion: In this population with predominantly high-risk AML, the combination of OM with a standard 7 + 3 regimen demonstrates a manageable safety profile with acceptable efficacy. As ~ 25% of patients achieving CR with '7 + 3' do so after a second induction (based on meta-analysis of 6 trials, n = 1980, see Cancer 2010, 116: 5012), the ORR here is comparable to those receiving a single standard of care induction. The results in this high-risk group are therefore promising and warrant further investigation in a phase II trial. At present, we are assessing leukemic blast MCL protein expression in stored pre-treatment samples to determine if this predicts OM efficacy. NCT02440568. Teva has performed a Medical Accuracy Review of this abstract. Figure. Figure. Disclosures Khan: Teva: Speakers Bureau. Patel:Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Honoraria.

Peritoneal metastases of colorectal origin – cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC). The financial aspect

2017 ◽  
Vol 89 (6) ◽  
pp. 1-6
Author(s):  
Tomasz Jastrzębski ◽  
Marek Bębenek
Keyword(s):  
Intraperitoneal Chemotherapy ◽  
Cytoreductive Surgery ◽  
Hyperthermic Intraperitoneal Chemotherapy ◽  
Distant Metastases ◽  
Peritoneal Metastases ◽  
Medical Procedures ◽  
Financial Loss ◽  
Colorectal Origin ◽  
Crs And Hipec ◽  
Financial Aspect

About 10% to 15% of patients with colon cancer have intraperitoneal metastases at diagnosis. The patients with intraperitoneal metastases and without distant metastases can benefit from cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Because up to a half of patients live for at least 5 years after this treatment, the treatment is used more and more often. The treatment of patients with intraperitoneal metastases with CRS and HIPEC costs more than the majority of other medical procedures, because CRS is extensive and takes a lot of time, and after surgery, patients need intensive care and expensive medications and equipment. Currently, only 40% to 80% of costs of CRS and HIPEC are reimbursed in Poland. Because CRS and HIPEC mean a financial loss to hospitals, they are rarely performed. We analyzed the costs of treating patients with peritoneal metastases by CRS and HIPEC in two centers (Gdank, Wroclaw) and showed how this treatment is reimbursed outside Poland. We discussed whether adequate qualification of patients and experience of the teams giving the treatment could reduce the costs.

Increased incidence of adverse events after concomitant hepatic arterial infusion plus systemic chemotherapy and bevacizumab for colorectal cancer with liver metastasis.

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 591-591
Author(s):  
S. Sadahiro ◽  
T. Suzuki ◽  
Y. Maeda ◽  
A. Tanaka ◽  
K. Okada ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Liver Metastasis ◽  
Adverse Events ◽  
Phase I ◽  
Systemic Chemotherapy ◽  
Response Rate ◽  
Hepatic Arterial Infusion ◽  
Progression Free Survival ◽  
Arterial Infusion ◽  
Grade 3

591 Background: FOLFOX+bevacizumab (BEV) is the standard systemic chemotherapy for metastatic colorectal cancer (CRC). We investigated the combination of FOLFOX4 and hepatic arterial infusion (HAI) in patients who had isolated liver metastasis from CRC. We also compared efficacy and safety between this combination therapy and its concomitant use with BEV. Methods: Twenty-five patients entered a phase I/II trial of HAI (5-FU 250 mg/d, leucovorin 25 mg/d; d1-7, q2w) combined with FOLFOX4. Fourteen other patients with a similar background received HAI + FOLFOX4 combined with BEV and the two regimens were compared. Results: In the phase I/II study, the recommended doses for FOLFOX were as follows: L-OHP, 85 mg/m2; l-LV, 100 mg/m2; 5-FU (bolus), 400 mg/m2; and 5-FU (infusion), 600 mg/m2. Sixteen patients who received this regimen showed a response rate of 93.8% (2 CR and 13 PR), a median progression-free survival of 323 days, and a one-year survival rate of 93.7%. In the subsequent phase II trial of HAI + FOLFOX4 with BEV, 14 patients were enrolled and the response rate was 78.6% (2 CR and 9 PR). The outcome was inferior when BEV was used concomitantly. The median numbers of doses were 10 (range: 1-27) for FOLFOX4 and 9 (1-27) for HAI without BEV, whereas the corresponding numbers with BEV were 8 (1-12) and 2 (0-9), respectively. There was a marked decrease in the number of HAI procedures when BEV was used. Thrombosis occurred in 8 patients who received concomitant BEV, which was the most common reason for cessation of HAI. Other adverse events (≥Grade 3) were neutropenia (n=7; 43.8%) and thrombocytopenia (n=2; 12.5%) without BEV or neutropenia (n=7; 43.8%) and diarrhea (n=1; 7.1%) with BEV, and no marked difference was seen between the two regimens. Both regimens were well tolerated. Severe neuropathy was only observed in 1 patient (6.3%; Grade 3) who received concomitant BEV. Conclusions: In the present study, HAI + FOLFOX combined with BEV caused thrombosis and disturbance of wound healing, thereby increasing the incidence of complications and making it difficult to continue treatment. These findings suggest that BEV should not be administered with HAI therapy. No significant financial relationships to disclose.

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