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Motixafortide and Pembrolizumab Combined to Nanoliposomal Irinotecan, Fluorouracil and Folinic Acid in Metastatic Pancreatic Cancer: the COMBAT/KEYNOTE-202 Trial

Bockorny, Bruno; Macarulla, Teresa; Semenisty, Valerya; Borazanci, Erkut; Feliu, Jaime; Ponz-Sarvise, Mariano; Gutierrez Abad, David; Oberstein, Paul; Alistar, Angela; Muñoz, Andres; Geva, Ravit; Guillen-Ponce, Carmen; Salgado, Mercedes; Peled, Amnon; Chaney, Marya; Gliko-Kabir, Irit; Shemesh-Darvish, Liron; Ickowicz, Debby; Sorani, Ella; Kadosh, Shaul; Vainstein, Abi; Hidalgo, Manuel
PURPOSE/OBJECTIVE:Pancreatic ductal adenocarcinoma (PDAC) is largely unresponsive to checkpoint inhibitors. Blockade of the CXCR4/CXCL12 axis increases intratumoral trafficking of activated T cells while restraining immunosuppressive elements. This study evaluates dual blockade of CXCR4 and PD1 with chemotherapy in PDAC. EXPERIMENTAL DESIGN/METHODS:Multicenter, single arm, phase II study to evaluate the safety and efficacy of motixafortide and pembrolizumab combined to chemotherapy in patients with de novo metastatic PDAC and disease progression on front-line gemcitabine-based therapy (NCT02826486). Subjects received a priming phase of motixafortide daily on days 1-5, followed by repeated cycles of motixafortide twice a week, pembrolizumab every 3 weeks, nanoliposomal irinotecan, fluorouracil and leucovorin every 2 weeks (NAPOLI-1 regimen). The primary objective was objective response rate (ORR). Secondary objectives included overall survival (OS), progression-free survival (PFS), disease control rate, safety and tolerability. RESULTS:A total of 43 patients were enrolled. The objective response rate according to RECISTv1.1 was 21.1% with confirmed ORR of 13.2%. The disease control rate was 63.2% with median duration of clinical benefit of 5.7 months. In the intention to treat population, median PFS was 3.8 months and median OS was 6.6 months. The triple combination was safe and well tolerated with toxicity comparable to the NAPOLI-1 regimen. Notably, the incidence of grade 3 or higher neutropenia and infection were 7%, lower than expected for this chemotherapy regimen. CONCLUSION/CONCLUSIONS:Triple combination of motixafortide, pembrolizumab and chemotherapy was safe, well tolerated and showed signs of efficacy in a population with poor prognosis and aggressive disease.
PMID: 34253578
ISSN: 1557-3265
CID: 4950402

Cancer surveillance awareness and practice among families at increased risk for pancreatic adenocarcinoma

Everett, Jessica N; Burgos, Gabriela; Chun, Jennifer; Baptiste, Ariele; Khanna, Lauren G; Oberstein, Paul E; Simeone, Diane M
BACKGROUND:Early detection of pancreatic ductal adenocarcinoma (PDAC) is an important goal for improving survival. Individuals who meet published guidelines for surveillance may be underidentified, and family communication about risk represents a pathway to increasing participation in surveillance. We investigated the uptake of and barriers to surveillance in at-risk relatives of clinic patients. METHODS:We conducted a retrospective record review of patients with personal or family history of PDAC evaluated over 12 months. The first relative presenting to clinic (proband) reported surveillance status and reasons for nonparticipation for at-risk relatives. Descriptive analyses and Fisher's exact tests were conducted to evaluate differences in surveillance participation. RESULTS:Among 193 at-risk relatives, 21% were in surveillance. The primary reasons for nonparticipation were lack of awareness (36%) and lack of interest (24%). Neither the sex nor the cancer status of probands impacted surveillance. At-risk relatives with familial pancreatic cancer (FPC) who also carried relevant pathogenic germline variants (PGVs) were more likely to undergo surveillance than those with FPC or PGVs alone (P = .003). Among families with PGVs, 59% of relatives potentially eligible for surveillance had not completed genetic testing. CONCLUSION/CONCLUSIONS:PDAC surveillance is underutilized in high-risk families. Communication interventions to address informational needs and decisional support could improve outcomes.
PMID: 33721345
ISSN: 1097-0142
CID: 4823462

Moving Beyond the Momentum: Innovative Approaches to Clinical Trial Implementation

Eng, Cathy; Chen, Emerson Y; Rogers, Jane; Lewis, Mark; Strosberg, Jonathan; Thota, Ramya; Krishnamurthi, Smitha; Oberstein, Paul; Govindarajan, Rang; Buchschacher, Gary; Patel, Sandip; Sohal, Davendra; Al-Toubah, Taymeyah; Philip, Philip; Dasari, Arvind; Kennecke, Hagan; Stein, Stacey
Despite efforts to enhance enrollment and the merger of national cooperative groups, < 5% of patients with cancer will enroll into a clinical trial. Additionally, clinical trials are affected by a lack of diversity inclusive of minority patients, rural residents, or low-income individuals. COVID-19 further exacerbated known barriers of reduced physician-patient interaction, physician availability, trial activation and enrollment, financial resources, and capacity for conducting research. Based on the cumulative insight of academic and community clinical researchers, we have created a white paper identifying existing challenges in clinical trial conduct and have provided specific recommendations of sustainable modifications to improve efficiency in the activation and conduct of clinical trials with an overarching goal of providing improved access and care to our patients with cancer.
PMID: 33534616
ISSN: 2688-1535
CID: 4814682

The Achilles' Heel of Pancreatic Cancer: Targeting pancreatic cancer's unique immunologic characteristics and metabolic dependencies in clinical trials

Siolas, Despina; Morrissey, Christy; Oberstein, Paul Eliezer
PMID: 33133736
ISSN: 2577-3577
CID: 4661202

Randomized Phase III Trial of Pegvorhyaluronidase Alfa With Nab-Paclitaxel Plus Gemcitabine for Patients With Hyaluronan-High Metastatic Pancreatic Adenocarcinoma

Van Cutsem, Eric; Tempero, Margaret A; Sigal, Darren; Oh, Do-Youn; Fazio, Nicola; Macarulla, Teresa; Hitre, Erika; Hammel, Pascal; Hendifar, Andrew E; Bates, Susan E; Li, Chung-Pin; Hingorani, Sunil R; de la Fouchardiere, Christelle; Kasi, Anup; Heinemann, Volker; Maraveyas, Anthony; Bahary, Nathan; Layos, Laura; Sahai, Vaibhav; Zheng, Lei; Lacy, Jill; Park, Joon Oh; Portales, Fabienne; Oberstein, Paul; Wu, Wilson; Chondros, Dimitrios; Bullock, Andrea J
PURPOSE/OBJECTIVE:To evaluate the efficacy and safety of pegvorhyaluronidase alfa (PEGPH20) plus nab-paclitaxel/gemcitabine (AG) in patients with hyaluronan-high metastatic pancreatic ductal adenocarcinoma (PDA). PATIENTS AND METHODS/METHODS:once per week. The primary end point was overall survival (OS); secondary end points included progression-free survival (PFS), objective response rate (ORR), and safety. Response was independently assessed per RECIST v1.1. RESULTS:3.8%). CONCLUSION/CONCLUSIONS:The addition of PEGPH20 to AG increased the ORR but did not improve OS or PFS. The safety profile of PEGPH20 plus AG was consistent with that found in previous studies. These results do not support additional development of PEGPH20 in metastatic PDA.
PMID: 32706635
ISSN: 1527-7755
CID: 4549242

Harmonic Motion Imaging of pancreatic tumor stiffness indicates disease state and treatment response

Payen, Thomas; Oberstein, Paul E; Saharkhiz, Niloufar; Palermo, Carmine F; Sastra, Stephen A; Han, Yang; Nabavizadeh, Alireza; Sagalovskiy, Irina R; Orelli, Barbara; Rosario, Vilma; Desrouilleres, Deborah; Remotti, Helen; Kluger, Michael D; Schrope, Beth A; Chabot, John A; Iuga, Alina C; Konofagou, Elisa; Olive, Kenneth P
PURPOSE/OBJECTIVE:Pancreatic ductal adenocarcinoma (PDA) is a common, deadly cancer that is challenging both to diagnose and to manage. Its hallmark is an expansive, desmoplastic stroma characterized by high mechanical stiffness. In this study, we sought to leverage this feature of PDA for two purposes: differential diagnosis and monitoring of response to treatment. EXPERIMENTAL DESIGN/METHODS:Harmonic Motion Imaging is a functional ultrasound technique that yields a quantitative relative measurement of stiffness suitable for comparisons between individuals and over time. We used HMI to quantify pancreatic stiffness in mouse models of pancreatitis and PDA as well as in a series of freshly resected human pancreatic cancer specimens. RESULTS:In mice, we learned that stiffness increased during progression from pre-neoplasia to adenocarcinoma, and also effectively distinguished PDA from several forms of pancreatitis. In human specimens, the distinction of tumors versus adjacent pancreatitis or normal pancreas tissue was even more stark. Moreover, in both mice and humans, stiffness increased in proportion to tumor size, indicating that tuning of mechanical stiffness is an ongoing process during tumor progression. Finally, using a brca2-mutant mouse model of PDA that is sensitive to cisplatin, we found that tissue stiffness decreases when tumors respond successfully to chemotherapy. Consistent with this observation, we found that tumor tissues from patients who had undergone neoadjuvant therapy were less stiff than those of untreated patients. CONCLUSIONS:These findings support further development of HMI for clinical applications in disease staging and treatment response assessment in pancreatic ductal adenocarcinoma.
PMID: 31831559
ISSN: 1078-0432
CID: 4238892

Tyme-88-Panc Part 2: A randomized phase II/III of SM-88 with MPS as third-line in metastatic PDAC [Meeting Abstract]

Pant, S; Chawla, S P; Chung, V; Del, Priore G; Kim, D W; Noel, M S; Oberstein, P E; Ocean, A J; Philip, P A; Picozzi, V J; Simeone, D M; Wang-Gillam, A
Background: Patients with metastatic pancreatic cancer who have progressed on two prior lines of therapy have a poor prognosis with an overall survival in the range of 2-2.5 months. (Manax, et al. J Clin Oncol 37, 2019 suppl 4; abstr 226). There is currently no standard of care for these patients that has demonstrated improved outcomes. SM-88 (D,Lalpha- metyrosine; racemetyrosine [USAN]) is a proprietary dysfunctional tyrosine derivative and is the backbone of SM-88 used with MPS (Methoxsalen 10mg, Phenytoin 50mg and Sirolimus 0.5mg; all administered daily). SM-88 monotherapy was relatively well tolerated, with improvement in survival in select patients with heavily pretreated PDAC who achieved stable disease on therapy (HR 0.08, p = 0.02). Circulating tumor cells (CTC's) were prognostic and decreased on therapy with SM-88 potentially identifying a subgroup of PDAC that may be most likely to benefit from therapy (Noel et al. Annal Oncol V30, Suppl 4, 2019). Preliminary radiomic analysis of the largest metastases at baseline suggested the same benefits including a correlation with baseline CTCs, changes in CTCs on therapy and OS (Ocean et al, Annal Oncol, V30, Suppl 5, 2019). Here, we describe a randomized, open-label, phase 2/3 trial evaluating the efficacy of SM-88 + MPS vs physician's choice treatment as third line therapy for patients with metastatic PDAC.
Method(s): This is a multi-center Phase 3 study of patients >=18 years with metastatic PDAC that progressed after 2nd lines of chemotherapy (gemcitabine [gem] and 5-fluorouracil [5-FU] based) with an ECOG <2. Randomization will be 1:1 with 250 patients being stratified by site, ECOG, and choice of chemotherapy. SM-88 will be administered at a dose of 460mg twice daily (920 mg/day). Primary end point is Overall Survival (OS). Secondary end points include progression free survival, response rate, duration of response, pharmacokinetics, safety and CTCs
ISSN: 1527-7755
CID: 4326252

Demoralization and depression in pancreatic cancer patients [Meeting Abstract]

Liu, J -Y; Placencio-Hickok, V; Anderson, B; Oberstein, P E; Coveler, A L; Denlinger, C S; Gong, J; Hendifar, A E
Background: Demoralization is a maladaptive coping response to stressful situations characterized by thoughts of hopelessness, helplessness, and loss of meaning and purpose. Psychometrically, it is measured using the Demoralization-Scale II (DS-II), a validated questionnaire that yields a patientreported quantification (scale 0-32) of demoralization. Previous studies involving patients with progressive disease have uncovered a strong positive correlation between demoralization and depression, respectively measured by the DS-II and Patient Health Questionnaire-9 (PHQ-9) surveys. Here, we aim to characterize demoralization and its relationship to depression in pancreatic cancer patients, a unique patient population in terms of its poor prognosis. We hypothesize that demoralization is highly prevalent in the pancreatic cancer patient population and strongly correlated with depression.
Method(s): Eligible patients with an active pancreatic cancer diagnosis, after consenting to an IRB approved protocol, will be administered the DS-II and PHQ-9 surveys to yield psychometric measurements for analysis. The primary objective of this project is to determine the association between demoralization (DS-II) and depression (PHQ-9) in pancreatic cancer patients. Secondary objectives include associations between demoralization and ethnicity, sexual orientation, suicidal ideation, education, cancer stage, and disease progression. Data will be analyzed via simple linear regression. An ANOVA will also be conducted using DS-II groups as the categorical variable and PHQ-9 scores as the continuous variable, and vice versa. This is a multi-institutional study to be conducted at Cedars- Sinai Medical Center, New York University, University of Washington, UC San Francisco, and Lewis Katz Schools of Medicine
ISSN: 1527-7755
CID: 4326242

A phase II, randomized, controlled trial of nivolumab in combination with BMS-986253 or cabiralizumab in advanced hepatocellular carcinoma (HCC) patients [Meeting Abstract]

Welling, T; Beri, N; Siolas, D; Cohen, D J; Becker, D J; Zhong, H; Wu, J J; Oberstein, P E; Karasic, T B
Background: Tyrosine kinase inhibitors can prolong survival in advanced HCC patients, but response rates have been minimal. Recently, immune checkpoint inhibition with nivolumab (nivo) demonstrated objective response rates (ORR) of 15% (escalation phase) and 20% (expansion phase) in the Checkmate 040 study. Pre-clinical and translational studies have demonstrated that IL-8 and tumor associated macrophages (TAMs) contribute to HCC progression and recurrence following treatment. Therefore, rationale exists to evaluate combinatorial approaches to target TAM function combined with checkpoint inhibitory therapy. This phase II, randomized study will evaluate the safety and efficacy of combined anti-CSF1R (Cabiralizumab) or anti-IL-8 (BMS-986253) in combination with Nivo in advanced HCC.
Method(s): Advanced HCC patients without prior systemic treatment and disease measurable by RECISTv1.1 with Childs A liver function are eligible. Patients will be enrolled (n=25 per arm) to Nivo 240 mg IV Q2 weeks monotherapy, Nivo 240 mg IV + BMS-986253 1200 mg IV Q2 weeks, or Nivo 240 mg IV + Cabiralizumab 4 mg/kg IV Q2 weeks. Primary endpoints include safety and ORR determined by RECISTv1.1. Secondary endpoints include time to response, duration of response, progression free survival, and overall survival. Exploratory endpoints include analysis of tumor microenvironment immune and tumor cell profiling of pre- and on-treatment tumor tissue
ISSN: 1527-7755
CID: 4326202

A phase I/II multisite study of nivolumab and carboplatin/paclitaxel with radiation therapy (RT) in patients with locally advanced esophageal squamous cell carcinoma (ESCC) [Meeting Abstract]

Wu, J J; Atkinson, E C; Leichman, L P; Patel, H; Iqbal, S; Lee, Du K; Bizekis, C; Goldberg, J D; Thomas, C R; Cohen, D J; Becker, D J; Siolas, D; Beri, N; Oberstein, P E; Ku, G Y
Background: Preoperative chemoRT is a standardof- care as shown in the CROSS trial (N Engl J Med 2012;366:2074-2084), Surgery is sometimes deferred in pts with clinical CR (cCR) based on lack of overall survival benefit (J Clin Oncol 2005;23:2310-2317, J Clin Oncol2007;25:1160-1168). Nivolumab has activity in advanced ESCC (Lancet Oncol 2017;18:631-639), and adding it to chemoRT may improve outcomes.
Method(s): This phase I/II study was designed to assess the safety and tolerability and efficacy of nivolumab added to chemoRT (6 weekly carboplatin AUC 2, paclitaxel 50mg/m2, RT 50.4 Gy in 1.8 Gy fractions 5/7 days) for pts with TanyN1-3 or T3-4N0M0 ESCC. The phase I primary endpoint is 'unacceptable toxicity' at 28 days after the last dose of chemotherapy. The phase II primary endpoints are cCR (endoscopy + PET/CT) and pCR rates for pts undergoing surgery. Nivolumab is given q2W x2, then concurrent chemoRT with nivolumab q2W x3. If no cCR, pt proceeds to esophagectomy, then adjuvant nivolumab q2W x3; if cCR, pt has an option of no surgery but receives nivolumab q2W x3.
Result(s):From 7/20/17 to 12/27/18, 6 pts were enrolled. No unacceptable or grade 5 toxicities were observed. The most common grade 1/2 AEs in >1 pt were anorexia, myelosuppression, elevated AST and nausea. Grade 3/4 AEs in >1 pt were lymphopenia and leukocytopenia. 2 pts required hospitalizations (dyspnea 1, colitis 1). All pts completed therapy; 1 pt had dose delay due to grade 2 esophagitis; 2 pts progressed, 4 achieved cCR. Of 4 pts with cCR, 2 pts chose surgery and both achieved pCR. None of the 4 pts recurred.
Conclusion(s): ChemoRT with nivolumab is tolerable with manageable toxicities in locally advanced ESCC. Enrollment to the phase II portion ended because of slow accrual. Adverse Events. Grade 1 &2 in > 1 pt: 4/6: Anorexia & Anemia 3/6: Leukocytopenia Neutropenia Thrombocytopenia Nausea & Elevated AST 2/6: Hypomagnesemia Hypokalemia Grade 3 & 4 in > 1 pt: 5/6: Lymphopenia, 2/6: Leukocytopenia
ISSN: 1527-7755
CID: 4326192