Publications by authors named "Paul H Frankel"

Introduction: Low grade serous ovarian carcinoma (LGSOC) is a rare subtype of ovarian cancer (OC) that is challenging to treat due to its relative chemoresistance. Given that LGSOC patients often recur in the peritoneal cavity, novel intraperitoneal (IP) chemotherapy should be explored. Pressurized intraperitoneal aerosolized chemotherapy (PIPAC) is a method that has demonstrated peritoneal disease control in cancers with peritoneal metastases.

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  • The study tested the combination of mirvetuximab soravtansine (MIRV) and gemcitabine on patients with hard-to-treat recurrent platinum-resistant epithelial ovarian cancer, endometrial cancer, and triple-negative breast cancer to find the maximum tolerated dose (MTD) and the recommended dose for further studies (RP2D).
  • Of the 20 patients enrolled, most had already undergone multiple chemotherapy treatments, with 45% achieving a partial response to the treatment; common side effects included anemia, neutropenia, and diarrhea.
  • The results suggest that while MIRV and gemcitabine show potential effectiveness in treating platinum-resistant ovarian cancer, they also lead
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Background: Pressurized intraperitoneal aerosolized chemotherapy (PIPAC) is a laparoscopic locoregional treatment for peritoneal metastases (PM) from colorectal cancer (CRC) or appendiceal cancer (AC) in patients who cannot undergo cytoreductive surgery (CRS). While PIPAC has been studied in Europe and Asia, it has not been investigated in the USA.

Patients And Methods: We evaluated PIPAC with 90 mg/m oxaliplatin alone (cycle 1) and preceded by systemic chemotherapy with fluorouracil (5-FU) and leucovorin (LV) (cycle 2-3) as a multicenter prospective phase I clinical trial (NCT04329494).

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  • The study investigates the combination of pembrolizumab (an immune checkpoint inhibitor) and doxorubicin (a chemotherapy drug) for treating metastatic triple-negative breast cancer (mTNBC) in patients who have not previously received anthracycline chemotherapy.
  • Results showed a promising overall response rate of 67%, with one complete response and five partial responses, alongside manageable safety profiles and common side effects like neutropenia and fatigue.
  • Immunological analysis indicated a significant increase in certain T cell populations, suggesting that the treatment not only works effectively but also stimulates the immune system in a beneficial way.
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Background: This trial evaluated the safety and efficacy of ipatasertib in combination with carboplatin, carboplatin/paclitaxel, or capecitabine/atezolizumab in patients with metastatic triple-negative breast cancer (mTNBC).

Methods: Eligibility criteria were mTNBC, RECIST 1.1 measurable disease, no prior use of platinum for metastatic disease (Arms A and B), and no prior exposure to immune checkpoint inhibitor (Arm C).

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  • - The study analyzed individual patient data from various Phase II trials by the California Cancer Consortium between 2005-2020 to examine how the order of patient entry (quartiles) affects clinical outcomes in stem-cell transplantation for renal-cell carcinoma.
  • - Researchers found that 90.6% of participants discontinued treatment, primarily due to disease progression or toxicity, with an increasing risk of discontinuation correlated with later quartiles of entry (Hazards Ratio 1.13 for each quartile, reaching 1.46 in Quartile 4).
  • - The study concluded that clinical outcomes deteriorate as patients enter later quartiles in Phase II trials, suggesting the need for further research to understand this trend and replicate the findings. *
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Objectives: Peritoneal metastasis (PM) from appendiceal cancer or colorectal cancer (CRC) has significant morbidity and limited survival. Pressurized intraperitoneal aerosolized chemotherapy (PIPAC) is a minimally invasive approach to treat PM. We aim to conduct a dose-escalation trial of mitomycin C (MMC)-PIPAC combined with systemic chemotherapy (FOLFIRI) in patients with PM from appendiceal cancer or CRC.

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Background: The objective of this study was to evaluate the safety and efficacy of nab-paclitaxel, trastuzumab, and pertuzumab as neoadjuvant therapy (NAT) in patients with human epidermal growth factor receptor 2 HER2+ breast cancer (HER2+ BC) to determine pathologic complete response (pCR), invasive disease-free survival (iDFS), and overall survival.

Methods: Forty-five patients with HER2+ BC Stages II-III were to be enrolled from 2013 to 2017. Patients were treated with weekly nab-paclitaxel (100 mg/m intravenously), weekly trastuzumab (4 mg/kg loading dose, then 2 mg/kg), and six cycles of pertuzumab (840 mg loading dose, then 420 mg intravenously day 1 every 21 days).

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PET imaging using radiolabeled immunoconstructs shows promise in cancer detection and in assessing tumor response to therapies. The authors report the first-in-human pilot study evaluating M5A, a humanized anti-carcinoembryonic antigen (CEA) monoclonal antibody (mAb), radiolabeled with Cu in patients with CEA-expressing malignancies. The purpose of this pilot study was to identify the preferred patient population for further evaluation of this agent in an expanded trial.

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This study investigated the safety and antitumor activity of aromatase inhibitors (AI) with immune checkpoint inhibitor (ICI) pembrolizumab in patients with hormone receptor positive (HR) human epidermal growth factor receptor 2-negative (HER2) metastatic breast cancer (MBC) in a phase II study with a safety lead-in (NCT02648477). Patients received pembrolizumab plus AI up to 2 years or until confirmed progression or unacceptable toxicity. Key eligibility criteria were HR HER2 MBC; RECIST v1.

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The presence of pathogenic variants (PVs) in triple-negative breast cancer (TNBC) is associated with a distinctive genomic profile that makes the tumor particularly susceptible to DNA-damaging treatments. However, patients with PVs can develop treatment resistance through the appearance of reversion mutations and restored expression. As copy-number variants (CNV) could be less susceptible to reversion mutations than point mutations, we hypothesize that carriers of CNVs may have improved survival after treatment compared to carriers of other PVs or wild-type.

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Cell-mediated immunity may contribute to providing protection against SARS-CoV-2 and its variants of concern (VOC). We developed COH04S1, a synthetic multiantigen modified vaccinia Ankara (MVA)-based COVID-19 vaccine that stimulated potent spike (S) and nucleocapsid (N) antigen-specific humoral and cellular immunity in a phase 1 clinical trial in healthy adults. Here, we show that individuals vaccinated with COH04S1 or mRNA vaccine BNT162b2 maintain robust cross-reactive cellular immunity for six or more months post-vaccination.

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Cyclin-dependent kinase 4/6 inhibitors are the standard of care for hormone receptor-positive metastatic breast cancer. This retrospective study reports on genomic biomarkers of CDK 4/6i resistance utilizing genomic data acquired through routine clinical practice. Patients with HR+ MBC treated with palbociclib, ribociclib, or abemaciclib and antiestrogen therapy were identified.

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Background: COH04S1, a synthetic attenuated modified vaccinia virus Ankara vector co-expressing SARS-CoV-2 spike and nucleocapsid antigens, was tested for safety and immunogenicity in healthy adults.

Methods: This combined open-label and randomised, phase 1 trial was done at the City of Hope Comprehensive Cancer Center (Duarte, CA, USA). We included participants aged 18-54 years with a negative SARS-CoV-2 antibody and PCR test, normal haematology and chemistry panels, a normal electrocardiogram and troponin concentration, negative pregnancy test if female, body-mass index of 30 kg/m or less, and no modified vaccinia virus Ankara or poxvirus vaccine in the past 12 months.

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We hypothesized that functional imaging with Cu-DOTA-trastuzumab PET/CT would predict the response to the antibody-drug conjugate trastuzumab-emtansine (T-DM1). Ten women with metastatic human epidermal growth factor receptor 2-positive breast cancer underwent F-FDG PET/CT and Cu-DOTA-trastuzumab PET/CT on days 1 and 2 before treatment with T-DM1. T-DM1-responsive patients had higher uptake than nonresponsive patients.

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Importance: Preclinical studies suggest that inhibition of single-stranded DNA repair by ataxia telangiectasia and Rad3 (ATR) may enhance the cytotoxicity of cisplatin, gemcitabine, and other chemotherapeutic agents. Cisplatin with gemcitabine remains the standard up-front therapy for treatment in patients with metastatic urothelial cancer.

Objective: To determine whether the use of the selective ATR inhibitor, berzosertib, could augment the activity of cisplatin with gemcitabine.

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Background: CDK4/6 inhibitors modulate immune response in breast cancer. This phase I/II trial was designed to test the safety and efficacy of palbociclib, pembrolizumab and letrozole in women with hormone receptor positive (HR) human epidermal growth factor receptor 2 negative (HER2) metastatic breast cancer (MBC).

Patients And Methods: Women with stage IV HR HER2 MBC were enrolled and treated with palbociclib, pembrolizumab and letrozole.

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Lessons Learned: The combination of enobosarm and pembrolizumab was well tolerated and showed a modest clinical benefit rate of 25% at 16 weeks. Future trials investigating androgen receptor-targeted therapy in combination with immune checkpoint inhibitors are warranted.

Background: Luminal androgen receptor is a distinct molecular subtype of triple-negative breast cancer (TNBC) defined by overexpression of androgen receptor (AR).

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Background: In this phase II clinical trial, we evaluated the efficacy of the nonanthracycline combination of carboplatin and nab-paclitaxel in early stage triple-negative breast cancer (TNBC).

Patients And Methods: Patients with newly diagnosed stage II-III TNBC (n = 69) were treated with neoadjuvant carboplatin (area under the curve 6) every 28 days for four cycles plus nab-paclitaxel (100 mg/m ) weekly for 16 weeks. Pathological complete response (pCR) and residual cancer burden (RCB) were analyzed with germline mutation status, tumor-infiltrating lymphocytes (TILs), TNBC molecular subtype, and GeparSixto immune signature (GSIS).

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Background: There is increasing use of Phase I statistical designs to find a dose that causes rapidly emerging and particularly concerning severe or life-threatening toxicities (dose-limiting toxicities, DLTs) in a specified percent of patients most commonly 25%. While a convenient statistical framework, the foundation for selecting any specified target DLT rate, and its relevance to the recommended Phase II dose is generally lacking.

Method: We surveyed 78 medical oncologists, most (69%) with experience as a principal investigator on a Phase I study, to ascertain their opinions related to this approach to Phase I studies and the targets often chosen.

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Importance: Phase 1 cancer studies, which guide dose selection for subsequent studies, are almost 3 times more prevalent than phase 3 studies and have a median study duration considerably longer than 2 years, which constitutes a major component of drug development time.

Objective: To discern a method to reduce the duration of phase 1 studies in adult and pediatric cancer studies without violating risk limits by better accommodating the accrual and evaluation process (or queue).

Design: The process modeled, the phase 1 queue (IQ), includes patient interarrival time, screening, and dose-limiting toxicity evaluation.

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The evolutionary changes in immune profiles of triple negative breast cancer (TNBC) are not well understood, although it is known that immune checkpoint inhibitors have diminished activity in heavily pre-treated TNBC patients. This study was designed to characterize immune profile changes of longitudinal tumor specimens by studying immune subsets of tumor infiltrating lymphocytes (TILs) in paired primary and metastatic TNBC in a cohort of "poor outcome" (relapsed within 5 years) patients. Immune profiles of TNBCs in a cohort of "good outcome" (no relapse within 5 years) patients were also analyzed.

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M5A is a humanized monoclonal antibody (mAb) directed against carcinoembryonic antigen (CEA) The purpose of this first in human phase I dose-escalation trial was to characterize the toxicities and determine the maximum tolerated dose (MTD) of yttrium-90 (Y)-DOTA-M5A as a single agent and in combination with gemcitabine (gem). Patients with advanced metastatic CEA-producing malignancies who had progressed on standard therapies were first administered indium-111 (In)-DOTA-M5A. If tumor targeting was observed, the patient then received the therapy dose of Y-DOTA-M5A.

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