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Byline: Robert P. Whitehead (1), Sheryl McCoy (2,10), John S. Macdonald (3), Saul E. Rivkin (4), Marcus A. Neubauer (5), Shaker R. Dakhil (6), Heinz-Josef Lenz (7), Michael S. Tanaka (8), James L. Abbruzzese (9) Abstract: Purpose: The purpose of this Phase II multi-institutional trial was to determine the efficacy and toxicity of R115777 in previously untreated patients with metastatic colorectal carcinoma. Patients and methods: Patients were required to have histologically confirmed colorectal cancer with distant metastatic disease that was not surgically curable. They could not have received prior chemotherapy for metastatic disease. R115777 was given at a dose of 300 mg p.o. twice a day for 21days every 28 days until tumor progression or toxicity or other reason for discontinuation occurred. The primary endpoint was to determine the confirmed response probability with this treatment. Results: There were 55 eligible patients accrued to the study. There were no complete responses, but one confirmed partial response for a confirmed response probability of 2% (95%CI 0--10%). Three additional patients had an unconfirmed partial response for an overall response probability of 7%. The time to treatment failure was 1.7 months and the estimated median survival was 8.1 months. One patient died of treatment related infection and there were 7 other patients with grade 4 toxicities consisting of neutropenia, leukopenia, febrile neutropenia and thrombocytopenia, depression, increased bilirubin, anemia, and pneumonitis/infiltrates. Conclusion: R115777 given as a single agent by this dose and schedule is ineffective in patients with metastatic colorectal cancer. Author Affiliation: (1) Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX (2) Southwest Oncology Group Statistical Center, Seattle, WA (3) St. Vincent's Comprehensive Cancer Center, New York, NY (4) Puget Sound Oncology Consortium, Seattle, WA (5) Kansas City Community Clinical Oncology Program, Kansas City, MO (6) Wichita Community Clinical Oncology Program, Wichita, KS (7) USC/Norris Comprehensive Cancer Center, Los Angeles, CA (8) University of California Davis Cancer Center, Sacramento, CA (9) University of Texas M.D. Anderson Cancer Center, Houston, TX (10) Operations Office, Southwest Oncology Group (SWOG-S9923), 14980 Omricon Drive, San Antonio, Texas, 78245-3217 Article History: Registration Date: 01/01/2005 Online Date: 28/01/2006

Byline: Robert P. Whitehead (1), Jacqueline K. Benedetti (2), James L. Abbruzzese (3), Bach Ardalan (4), J. Wendall Goodwin (5), Stanley P. Balcerzak (6), Wolfram E. Samlowski (7), Heinz-Josef Lenz (8), John S. Macdonald (9) Keywords: 5-FU; leucovorin; PALA; pancreas cancer; phase II Abstract: Purpose: The purpose of this phase II multi-institutional study was to define the efficacy and toxicity of infusional 5-FU in combination with PALA and leucovorin in patients with advanced pancreatic cancer. Patients and methods: Patients were required to have histologically confirmed pancreatic cancer that was locally advanced, unresectable or disseminated. The treatment regimen consisted of weekly 5-FU 2600 mg/m.sup.2 given concurrently with leucovorin at 500 mg/m.sup.2. Both drugs were administered by 24-hour continuous infusion. PALA was administered 24 hours prior to the administration of 5-FU/LV at a dose of 250 mg/m.sup.2 IV over 15 minutes weekly. Patients were continued on the assigned treatment regimen until progression of disease, unacceptable toxicity, or the patient declined further therapy. Results: This study accrued 30 patients. Four of these patients were ineligible. All 26 eligible patients were evaluated for toxicity. One patient had inadequate assessment of response and was considered a non-responder. Three of the twenty-six eligible patients had partial responses, for a response rate of 12% (95% confidence interval 2% to 30%). All 26 eligible patients have died and the median overall survival was 7 months (95% confidence interval: 5.2 to 9 months). Four patients experienced grade 4 toxicities, including bilirubin increase (2 patients), vomiting (1 patient) and non-local skin ulceration (1). Two patients discontinued therapy due to toxicity. Conclusion: The dual modulation of 5-FU with PALA and leucovorin in the dose and schedule used here, has a response rate similar to other single agents in pancreatic cancer and can result in some long term survival while having relatively mild toxicity. Author Affiliation: (1) University of Texas Medical Branch, Galveston, TX (2) Southwest Oncology Group Statistical Center, Seattle, WA (3) University of Texas, MD Anderson Cancer Center, Houston, TX (4) School of Medicine, University of Miami, Miami, FL (5) Ozarks Regional Clinical Oncology Program, USA (6) Ohio State University Health Center, Columbus, OH (7) University of Utah Health Sciences Center, Salt Lake City, UT (8) University of Southern California School of Medicine, Los Angeles, CA (9) St. Vincent's Comprehensive Cancer Center, New York, NY Article History: Registration Date: 21/10/2004

Summary: Vantictumab is a fully human monoclonal antibody that inhibits Wnt pathway signaling through binding FZD1, 2, 5, 7, and 8 receptors. This phase Ib study evaluated vantictumab in combination with nab-paclitaxel and gemcitabine in patients with untreated metastatic pancreatic adenocarcinoma. Patients received vantictumab at escalating doses in combination with standard dosing of nab-paclitaxel and gemcitabine according to a 3 + 3 design. A total of 31 patients were treated in 5 dosing cohorts. Fragility fractures attributed to vantictumab occurred in 2 patients in Cohort 2 (7 mg/kg every 2 weeks), and this maximum administered dose (MAD) on study was considered unsafe. The dosing schedule was revised to every 4 weeks for Cohorts 3 through 5, with additional bone safety parameters added. Sequential dosing of vantictumab followed by nab-paclitaxel and gemcitabine was also explored. No fragility fractures attributed to vantictumab occurred in these cohorts; pathologic fracture not attributed to vantictumab was documented in 2 patients. The study was ultimately terminated due to concerns around bone-related safety, and thus the maximum tolerated dose (MTD) of the combination was not determined. The MAD of vantictumab according to the revised dosing schedule was 5 mg/kg (n = 16). [ABSTRACT FROM AUTHOR]

Antiangiogenic drugs may cause vascular normalization and correct hypoxia in tumors, shifting cells to mitochondrial respiration as the primary source of energy. In turn, the addition of an inhibitor of mitochondrial respiration to antiangiogenic therapy holds potential to induce synthetic lethality. This study evaluated the mitochondrial inhibitor ME-344 in combination with bevacizumab in patients with refractory metastatic colorectal cancer (mCRC). Patients were eligible if they had disease progression after standard therapies, adequate hematologic, hepatic and renal function, and no contraindications to bevacizumab. ME-344 was administered intravenously on days 1, 8 and 15 and bevacizumab on days 1 and 15 of 28-day cycles until disease progression or intolerance. The primary efficacy endpoint was progression-free survival (PFS) at week 16. In the 23 patients enrolled, the median age was 58 years, median number of prior lines of therapy was 4, and median interval from last therapy was 3 months. The most common adverse events (all grades/grade ≥ 3) were fatigue (48%/13%), abdominal pain (35%/4%), diarrhea (30%/4%) and constipation (30%/0%). No patient had an objective response; 9 patients (39%) achieved stable disease. The 16-week PFS was 30.6% (95% confidence interval [CI]: 12.2-51.3), the median PFS was 1.9 months (95% CI: 1.6-4.7), and the median overall survival was 6.7 months (95% CI: 3.4-not reached). ME-344 plus bevacizumab was well tolerated. Disease control was limited in this heavily pretreated patient population. Additional investigations in earlier lines are indicated, and extended-release ME-344 formulations may provide longer drug exposure to maximize benefit. (Trial registration number ClinicalTrials.gov NCT05824559. Registration date 22 March 2022)., Competing Interests: Declarations. Ethical approval: This study was performed in line with the ethical principles that have their origin in the Declaration of Helsinki, and the ICH Harmonised Tripartite Guideline for GCP and all applicable regulations. This study and all pertinent documents were reviewed and approved by the Institutional Review Board of each participating institution. Consent to participate: All participants provided written informed consent to participate in the study prior to the initiation of any study-specific procedures. Competing interests: Patrick M. Boland is on the advisory board of AbbVie, Bristol Myers Squib, BeiGene and Taiho and has a research grant from CARIS. Kristen K. Ciombor is a consultant/advisory board for Pfizer, Incyte, Exelixis, Bayer, ALX, Tempus, Taiho, Agenus, Merck, Beigene, and has received research grants from BMS, Array, Incyte, Daiichi Sankyo, Nucana, Merck, Pfizer, Calithera, Genentech, Seagen, and Syndax. Vaia Florou is a consultant/advisory board member of Deciphera, Springwork Therapeutics, and Aadi Biosciences. Michael J. Pishvaian is a consultant/ad hoc advisory board for Astra Zeneca, Ideaya, Seattle Genetics, Merus, Merck, Moderna, Pfizer, Novartis, Astellas, and Serna Bio. He is on the Steering Committee/Advisory Board for Astellas and Merck. He has received travel, accommodations and expenses support from Astellas and RenovoRx. He owns equity in Perthera. He has received institutional research funding from Tesaro, Arcus Bio, Ideaya, Repare Tx, Novartis, Pfizer, Merck, Tizonia, Biomed Valley Discoveries, Amgen, RenovoRx, Boerhinger Ingelheim, Astellas, Hutchinson Medipharma, Takeda, Actuate, MEI Pharma, Elevation Oncology, and Recursion Pharma. Min Tang and Prabu Rajagopalan are consultants to MEI Pharma. Sandy E. Wiley and Richard G. Ghalie are employed by and hold equity in MEI Pharma. Howard S. Hochster is consultant to GSK, AstraZeneca, Processa and Compass Therapeutics, and is expert witness for Guardant. Heinz-Josef Lenz, Michael Cusnir, Dierdre Cohen, and Jessie Y. Guo have no conflicts to disclose., (© 2024. The Author(s).)