Step Counts Correlated With QoL With SM-88 in Metastatic Pancreatic Cancer

Vincent Chung, MD

Step counts appeared to correlate with self-reported quality of life (QoL) during the first 2 weeks of treatment with SM-88 (racemetyrosine) in patients with metastatic pancreatic cancer, the results of a preliminary exploratory analysis from part 2 of the phase 2/3 TYME-88-Panc trial (NCT03512756) showed. Findings were presented during the 2021 Gastrointestinal Cancers Symposium.¹

All patients who enrolled on the trial and received treatment with SM-88 were given wearable devices to passively capture biometric data. Of these patients, 16 were synchronized on cycle 1 day 1, 20 had available data that was synchronized within the first 2 weeks, and 1 patient did not have the technical support available to collect information.

The median baseline daily step count during the first 2 weeks of treatment with SM-88 was 3993.8 in patients who were alive (IQR, 2745.6-5078) versus 689.3 in patients who died (IQR, 630.0-2083.6) among those determined to be evaluable who had available data. Moreover, passively acquired mean heart rate during the third week of the trial among patients who died early was 89.3 (standard deviation [SD], 10.5) compared with 78.0 (SD, 9.2) in patients who were still alive. The medians were 87.0 and 79.2 for each cohort, respectively (P = NS).

When patients were asked question 29 (Q29) from the European Organization of Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ), which focused on overall health, during the second cycle, a median score of 3 was reported in patients who experienced early death versus 4.5 in those who were still alive. Moreover, mean steps during the first 2 weeks was found to be correlated with EORTC Q30 responses (r = 0.71; P = .01). From cycle 1 to cycle 2, patients who experienced early death had a median weight decrease of 2.5 lbs compared with 0.5 lbs in those who were still alive.

“Median daily baseline step counts were calculated for the first 2 weeks of treatment,” Vincent Chung, MD, an associate clinical professor in the Department of Medical Oncology & Therapeutics Research and director of the Phase I Program at City of Hope, said during a presentation at the meeting. “Even though the eligible patients enrolled had an ECOG performance status of 0-1, the subjects who died early had step counts that were 5 times less than that of the comparator group.”

SM-88 is an investigational dysfunctional tyrosine derivative that is given with 10 mg of methoxsalen (Oxsoralen), 50 mg of phenytoin (Dilantin), and 0.5 mg of sirolimus (Rapamune). The agent was developed to interrupt protein synthesis machinery, induce oxidative stress, and alter both autophagy and immune function.² Thus far, the agent has been shown to have a survival benefit with favorable tolerability in heavily pretreated patients with pancreatic ductal adenocarcinoma (PDAC) who had achieved stable disease (HR, 0.08; P = .02).³

Additionally, circulating tumor cells (CTCs) have demonstrated prognostic value in identifying a subgroup of patients with PDAC who may be more likely to glean benefit from SM-88. In a preliminary radiomic analysis, the largest metastases at baseline reportedly correlated with baseline CTCs.⁴

The prospective, open-label, randomized TYME-88-Panc trial is currently enrolling patients with histologically or cytologically confirmed PDAC who have received at least 2 prior lines of systemic therapy and have acceptable adequate organ function.

Patients will be randomized 1:1 to receive either SM-88 (n = ~125) or investigator's choice of therapy (n = ~125). Patients will receive treatment until intolerable toxicity, progressive disease, or until any treatment discontinuation criteria are met.

The primary end point of the study is overall survival, with key secondary end points consisting of progression-free survival, clinical benefit rate, and QoL. Additionally, key exploratory end points include a biomarker analysis, which is comprised of CTCs and wearable device data.

The goal of the preliminary analyses of the randomized portion of the trial was to examine the potential role of SM-88 in the treatment of patients with metastatic disease through the use of CTC analysis and biometrics data that had been passively collected through a wearable device with data available as of September 15, 2020.

In total, 27 patients had available CTC data. Investigators collected isolated CTCs on the first day of each treatment cycle. Four phenotypic CTCs were noted by investigators, including epithelial cell surface marker Epi-positive, green fluorescent labeled CAM (GCAM)-positive, Epi-positive floating fraction, and GCAM-positive floating fraction.

Biometrics data were available for 20 patients. These data were also passively collected and included information on total number of steps taken per day and heart rate. This information was collected through wearable technology, such as a Fitbit, that was continuously worn by patients. Investigators examined patients who died early during the trial; this was defined as those who passed away within 3 months of randomization versus those who did not.

Additionally, patients were asked 2 global questions from the EORTC QLQ-C30 to determine a correlation with biometric parameters. One was Q29, which was "How would you rate your overall health during the past week?” The other was Q30, which was "How would you rate your QoL during the past week?"

Patients enrolled on the study had a mean age of 65 years (range 48-86) and a mean body mass index of 24.6 (range 18.8-38.7). Of the patients enrolled, 39.5% were female and 60.5% were male. The majority of patients were white (76.3%) and 15.8% were Asian. Moreover, patients had a mean CA 19.9 of 23,678.2 (range, 2.9-422,000.4) and a mean albumin of 3.8 g/dL (range, 2.7-4.6).

As of September 15, 2020, 67 patients consented to treatment, 38 of whom were randomized and considered evaluable. Roughly half, or 52.6%, (n = 20/38) of all patients were randomized to receive 920 mg of daily SM-88, while the remainder (47.4%; n = 18/38) were treated with standard of care.

Additional data revealed that the 4 CTC subpopulation phenotypes identified by investigators, defined by GCAM positivity, EPI positivity, and cluster status, were enumerated and correlated with one another (r = 0.03-0.71). At least 1 CTC subpopulation was identified at baseline in patients who had available data (n = 27), at a mean of 33.8 cells/2 mL. It was also revealed that the longest metastatic lesion diameter at baseline correlated with baseline CTCs (Epi-positive cluster, r = 0.55; P = 0.05; GCAM-positive cluster, r = 0.52; P = .07). Investigators were able to successfully separate and enumerate CTCs at each subsequent treatment cycle for further evaluation.

Notably, 166 adverse effects (AEs) were reported in 25 of the 38 patients enrolled on the trial, of whom 14 (56.0%) were treated with SM-88 and 11 (44.0%) with standard of care. Among these AEs, 6.02% (n = 10) were determined to be serious, having been reported by 4 patients on each respective arm of the study.

Of the reported AEs, 25.7% were determined to potentially be related to SM-88, while the majority were considered to be possibly be related to the standard-of-care chemotherapy (50.8%; P = .001). All AEs possibly related to treatment with SM-88 were grade 1 or 2 in severity with the exception of 4 hematologic events, 1 liver function test (LFT), and 1 case of abdominal pain.

The most common AEs associated with SM-88 were gastrointestinal (GI; 26.9%), dermatologic (19.2), and LFTs (19.2%), while the most frequent AEs observed in the standard-of-care arm were GI (48.5%), hematologic (24.2%), and dermatologic (15.2%).

Investigators concluded that biometrics can be passively collected and that they appeared to correlate with traditional clinical trial outcomes. CTC collection and enumeration also demonstrated feasible correlation with traditional clinical trial outcomes.

Moreover, possible important predicators of CTCs could include radiologic feature analysis due to the fact that the longest patient lesion diameter appeared to correlate with CTCs at baseline. The agent was also found to be well tolerated within this population, having elicited no grade 4 or 5 AEs.

_References

_{1. Chung V, Oberstein PR, Lim KH, et al. Phase 2/3 study of SM-88 in patients with metastatic pancreatic cancer. Poster presenter at: 2021 Gastrointestinal Cancers Symposium; January 15-17, 2021; Virtual. Accessed January 15, 2021. Abstract #437. http://bit.ly/3nN1fkY}

_{2. Fernandez-Zapico M, Kim DW, Philip P, et al. Therapeutic potential of targeting amino acid metabolism in pancreatic cancer. Cancer Res. 2019;79(suppl 24):B15. doi:10.1158/1538-7445.PANCA19-B15}

_{3. Noel M, Wang-Gillam A, Ocean A, et al. SM-88 therapy in high-risk poor prognosis pancreatic cancer (PDAC). Ann of Oncol. 2019;30(suppl 4):IV16. doi:doi.org/10.1093/annonc/mdz155.058}

_{4. Ocean A, Noel M, Wang-Gillam A, et al. Phase II monotherapy efficacy of cancer metabolism targeting SM-88 in heavily pre-treated PDAC patients. Ann Oncol. 2019;30(suppl 5):V275. doi:10.1093/annonc/mdz247.046}