Abstract
Lessons Learned
This trial evaluating a novel plant extract, PBI‐05204, did not meet its primary endpoint of overall survival but did show signals of efficacy in heavily pretreated mPDA.
PBI‐05204 was generally well tolerated, with the most common side effects related to treatment being vomiting (23.7%), nausea (18.4%), decreased appetite (18.4%), and diarrhea (15.8%).
Additional trials are needed to explore the role of PBI‐05204 in cancer treatment.
Background
Survival for metastatic pancreatic ductal adenocarcinoma (mPDA) is dismal, and novel agents are needed. PBI‐05204 is a modified supercritical carbon dioxide extract of Nerium oleander leaves. Oleandrin, the extract's major cytotoxic component, is a cardiac glycoside that has demonstrated antitumor activity in various tumor cell lines with a mechanism involving inhibition of Akt phosphorylation and through downregulation of mTOR.
Methods
A phase II, single‐arm, open‐label study to determine the efficacy of PBI‐05204 in patients with refractory mPDA therapy was conducted. The primary endpoint was overall survival (OS), with the hypothesis that 50% of patients would be alive at 4.5 months. Secondary objectives included safety, progression‐free survival (PFS), and overall response rate. Patients received oral PBI‐05204 daily until progressive disease (PD), unacceptable toxicity, or patient withdrawal. Radiographic response was assessed every two cycles.
Results
Forty‐two patients were enrolled, and 38 were analyzed. Ten patients were alive at 4.5 months (26.3%) with a median PFS of 56 days. One objective response (2.6%) was observed for 162 days. Grade ≥ 3 treatment‐emergent adverse events occurred in 63.2% of patients with the most common being fatigue, vomiting, nausea, decreased appetite, and diarrhea.
Conclusion
PBI‐05204 did not meet its primary endpoint for OS in this study. Recent preclinical data indicate a role for PBI‐05204 against glioblastoma multiforme when combined with chemotherapy and radiotherapy. A randomized phase II trial is currently being designed.
Discussion
This study represents ongoing efforts in pancreatic cancer to discover new agents active in the disease as well as ones that are tolerable in a potentially fragile population. Table 1 displays both primary and secondary endpoint results. Figure 1 displays the Kaplan‐Meier curve for overall survival. As noted in the abstract, the study did not meet its primary endpoint of improved overall survival versus historical controls. A variety of factors likely influenced this outcome. Although the drug had demonstrated activity in preclinical models, the median number of previous chemotherapy regimens that patients had been treated with was three, indicating a heavily pretreated population. It is unclear if this drug would be more efficacious earlier in the treatment course. In addition, patients who were able to complete at least two cycles of the drug had improved outcomes. It is impossible to distinguish, of course, whether this was due to the drug or whether these patients had less aggressive disease at baseline. Lastly, PBI‐05204 appeared to work better in combination with cytotoxic chemotherapy in vitro. Whether this is the case in humans would need to be explored in subsequent studies. Numerous observations over decades of research have suggested the antineoplastic potential of cardiac glycosides, but as of now a firm role has not been established. Given the overall tolerability of PBI‐05204 and survival signal in a small percentage of patients, further studies are warranted to explore its therapeutic potential.
Table 1.
Endpoint results
| Assessment | Results |
|---|---|
| Primary endpoint, OS (patient survived 4.5 months or longer), n (%) | |
| Yes | 10 (26.3) a |
| No | 28 (73.7) |
| Secondary endpoints | |
| TTP, median, days (KM EFS %) | 112 (40.2) |
| TTF, median, days (KM EFS %) | 56 (25.0) |
| PFS, median, days (KM EFS %) | 56 (44.7) |
| ORR (CR + PR), n (%) | 1 (2.6) |
| TCR (CR + PR + SD), n (%) | 8 (21.1) |
| DOR, days | 162 days |
| CA 19‐9 response, n (%) | 1 (2.6) |
Posterior results probability: >0.5.
Abbreviations: CA 19‐9, cancer antigen 19‐9; CR, complete response; DOR, duration of response; KM EFS, Kaplan‐Meier event‐free survival estimate; ORR, overall response rate; OS, overall survival; PFS, progression‐free survival; PR, partial response; SD, stable disease; TCR, tumor control rate; TTF, time to failure; TTP, time to progression.
Figure 1.
Kaplan‐Meier curve: Overall survival.
Trial Information
| Disease | Pancreatic cancer |
| Stage of Disease/Treatment | Metastatic/advanced |
| Prior Therapy | No designated number of regimens |
| Type of Study – 1 | Phase II |
| Type of Study – 2 | Single arm |
| Primary Endpoint | Overall survival |
| Secondary Endpoints | Time to progression, time to failure, progression‐free survival, overall response rate, tumor control rate, duration of response, cancer antigen (CA) 19‐9 response, safety |
| Additional Details of Endpoints or Study Design | Endpoints: Overall response rate: complete response (CR) + partial response (PR); tumor control rate: CR + PR + stable disease (SD); CA 19‐9 response: defined as a decrease from baseline by ≥25%. |
| Prior therapy: no designated number of regimens was required; however, patients must have been relapsed from or refractory to standard therapy with no curative options or intolerant to or refuse standard chemotherapy. | |
| The primary hypothesis is that the proportion of patients with metastatic pancreatic adenocarcinoma surviving at 4.5 months is <0.5, which is chosen based on historical information. The analysis of the primary endpoint was performed on all patients who received one dose of study drug (full analysis set) via Bayesian analysis to compute the posterior probability that the true underlying mortality rate was less than 0.5. If the posterior probability exceeds 97%, the study would be considered positive. | |
| Investigator's Analysis | Level of activity did not meet planned endpoint |
Drug Information
| Drug 1 | |
| Generic/Working Name | PBI‐05204 |
| Company Name | Phoenix Biotechnology, Inc. |
| Drug Type | Biological |
| Drug Class | Other ‐ cardiac glycoside |
| Dose | 0.225 milligrams (mg) per kilogram (kg) |
| Route | Oral (p.o.) |
| Schedule of Administration | BID every day on a 28‐day cycle |
Patient Characteristics
| Number of Patients, Male | 20 |
| Number of Patients, Female | 18 |
| Stage |
Stage I: 0 Stage IIA: 0 Stage IIB: 0 Stage III: 0 Stage IV: 38 |
| Age | Median (range): 65.0 (44–86) |
| Number of Prior Systemic Therapies | Median (range): 3 (1–11) |
| Performance Status: ECOG |
0 — 12 1 — 26 2 — 3 — Unknown — |
| Cancer Types or Histologic Subtypes | Adenocarcinoma, 38 |
Primary Assessment Method
| Title | Full Analysis Set |
| Number of Patients Enrolled | 41 |
| Number of Patients Evaluable for Toxicity | 38 |
| Number of Patients Evaluated for Efficacy | 38 |
| Evaluation Method | RECIST 1.1 |
| Response Assessment CR | n = 0 (0%) |
| Response Assessment PR | n = 1 (3%) |
| Response assessment SD | n = 7 (18%) |
| Response Assessment PD | n = 21 (55%) |
| Response Assessment OTHER | n = 9 (24%) |
| (Median) Duration Assessments PFS | 56 days |
| (Median) Duration Assessments TTP | 112 days |
| (Median) Duration Assessments OS | 112 days |
| (Median) Duration Assessments Response Duration | 162 days |
| (Median) Duration Assessments Duration of Treatment | 59 days |
| Outcome Notes |
Landmark endpoints were selected—day 56 for PFS and day 112 for time to progression (TTP). Day 56 corresponds with first restaging for PFS. Day 112 corresponds with second restaging for TTP. |
| Adverse Events | Refer to Table 2. |
Assessment, Analysis, and Discussion
| Completion | Study completed |
| Investigator's Assessment | Level of activity did not meet planned endpoint |
Pancreatic cancer has one of the highest mortalities of all malignancies. It is estimated that 56,770 diagnoses were made and 45,750 deaths occurred in 2019 [1]. One analysis projects pancreatic cancer to surpass breast, prostate, and colorectal cancers as the leading cause of cancer‐related death in the U.S. by the year 2030 [2]. Current front‐line treatment options for metastatic pancreatic ductal adenocarcinoma (mPDA) include intravenous cytotoxic chemotherapy [3], with 5‐year overall survival estimates at 9% [4]. As such, novel approaches are needed to improve survival in this disease.
Cardiac glycosides have been of interest in the treatment of cancer since the late 1970s [5], when their activity was described in relation to breast cancer. PBI‐05204 (Phoenix Biotechnology, Inc., San Antonio, TX) is a modified supercritical carbon dioxide extract of Nerium oleander leaves. Oleandrin, the extract's major cytotoxic component, is a polyphenolic cardiac glycoside used in some countries to treat congestive heart failure, but it has also demonstrated tumor toxicity in preclinical studies [6, 7]. In a human pancreatic cancer Panc‐1 orthotopic model, this preparation reduced tumor burden alone and in combination with gemcitabine. Biomarker analysis in this preclinical study suggested that the compound exhibits its antineoplastic effects through downregulation of the PI3k/Akt and mTOR pathways [8].
A phase I clinical trial (3 + 3) of PBI‐05204 was completed in 46 patients with advanced solid tumors, demonstrating stable disease for ≥4 months in seven (15%) patients and tumor regression in three (6.5%) patients [9]. Doses ranged from 0.0083 to 0.3383 mg/kg per day, with a final recommended phase II dose (RP2D) of 0.2255 mg/kg per day. Most patients had adenocarcinomas (87%), with mPDA representing 13% of the cohort. The most common side effects were fatigue (56.5%), nausea (41.3%), and diarrhea (32.6%). Importantly, no significant cardiac toxicity was noted in this study. Two patients with mPDA had stable disease of ≥4 months [8]. Given the safety and preliminary signal found in the phase I setting for mPDA, a phase II trial was designed.
Here we present the results from a phase II, multicenter, single‐arm, open‐label, Bayesian adaptive efficacy and safety study of PBI‐05204 in patients with mPDA. Patients were eligible for inclusion if they were aged ≥18 years, had relapsed or refractory mPDA or refused standard treatment options, had a performance status of 0–1, and had measurable disease and a standard laboratory exam. Patients with uncontrolled cardiac disease, malabsorptive diarrhea, and chronic viral infection were excluded, along with routine exclusions. Drug was to be given at the RP2D of 0.2255 mg/kg per day by mouth in two divided doses each day in a 28‐day cycle. Disease was assessed every other cycle by the investigator using RECIST version 1.1. The first assessment was performed prior to the third cycle (~56 days). Drug was to be continued until progressive disease, toxicity, or withdrawal.
Endpoints were analyzed based on all patients who received at least one dose of drug (full analysis set), although additional analyses were performed on those who completed two cycles of therapy (per‐protocol set). The primary endpoint was overall survival (OS), with the primary hypothesis that PBI‐05204 would improve the proportion of patients with mPDA surviving at 4.5 months, relative to <0.5 based on historical data. Bayesian analysis was used to compute the posterior probability that the true underlying mortality rate is less than 0.5. Two interim analyses of the primary efficacy endpoint were planned, with predefined stopping criteria for lack of efficacy.
Forty‐two patients were enrolled at five centers from July 2015 to July 2016, and 38 were included in the final analysis (three patients never dosed, one excluded for incorrect diagnosis). Median age was 65.1 (range 44–86) years, and 52% were male. Most patients were white (76.3%), followed by black (10.5%) and Asian (7.8%). The median time since initial pancreatic cancer diagnosis was 16.9 months (range 1–100), with 21.1% having undergone previous curative‐intent resection. Over 80% had been on at least two lines of chemotherapy.
Only 10 (26.3%) patients survived >4.5 months, producing a posterior probability of 0.0017 for overall survival and a median value of 112 days. Median progression‐free survival was 56 days. One patient experienced a partial response, which lasted 162 days. One patient (2.6%) had a response in cancer antigen 19‐9, defined as a decrease by ≥25% from baseline. The most common reason for study withdrawal was progressive disease (45.2%). Of the 38 patients enrolled, only 13 (31%) completed two cycles of treatment. Interestingly, the majority of these survived >4.5 months (61.5%) with a median overall survival of 224 days.
The most common treatment‐emergent adverse events (TEAEs) related to the drug were vomiting (23.7%), nausea (18.4%), diarrhea (15.8%), and decreased appetite (18.4%). Over half of patients (55.3%) experienced at least one grade 3 or higher TEAE (23.7% gastrointestinal, 10.5% hematologic).
The most effective regimens in metastatic pancreatic cancer include doublet (gemcitabine/nab‐paclitaxel) and triplet (FOLFIRINOX) therapy. Hence, in a heavily pretreated population, monotherapy may be less likely to work, although potentially better tolerated. In preclinical studies, gemcitabine activity was enhanced with PBI‐05204 [7]. The majority of patients in this trial had already been exposed to gemcitabine, as are many patients with mPDA within their first two lines of treatment. Given the lack of clinical benefit with PBI‐05204 monotherapy, it is unclear if the combination would have shown more efficacy.
PBI‐05204 did not meet its primary endpoint for OS in this study, although there was a trend toward improved survival in those who completed two cycles of therapy. The drug was generally well tolerated, with predominately low‐grade gastrointestinal side effects. Recent preclinical data indicate an efficacious role for PBI‐05204 against glioblastoma multiforme when combined with chemotherapy, such as temozolomide, and radiotherapy. A randomized phase II trial is currently being designed.
Disclosures
Dana Backlund Cardin: Rafael Pharmaceuticals (C/A), Rafael Pharma, EMD Serono, Abbvie, Eli Lilly & Co. (RF); Erkut Hasan Borazanci: Imaging Endpoints (C/A), Ipsen (H), Mabvax, Bristol‐Myers Squibb, Merck, Corcept, Minneamrita, Fujifilm, Astrazeneca, Helix, Bioline, Daiichi Sankyo, Idera, Minneamrita, Pharmacyclics LLC, Pfizer, Eli Lilly & Co., Phoenix Biotechnology, Samumed, Seena Magowitz Foundation, TGen Foundation (RF), Invitae (SAB); Robert A. Newman: Phoenix Biotechnology (Chief Science Office, C/A, IP, OI). The other authors indicated no financial relationships.
(C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board
Table
Table 2.
Most common (>15%) adverse events
| Adverse event | All grades, n (%) | Grade 3–5, n (%) |
|---|---|---|
| Fatigue | 19 (50) | 0 |
| Vomiting | 18 (47.4) | 3 (7.9) |
| Decreased appetite | 14 (36.8) | 0 |
| Nausea | 12 (31.6) | 5 (13.2) |
| Abdominal pain | 11 (28.9) | 2 (5.3) |
| Diarrhea | 10 (26.3) | 1 (2.6) |
| Back pain | 9 (23.7) | 0 |
| Dehydration | 8 (21.1) | 3 (7.9) |
| Cough | 7 (18.4) | 1 (2.6) |
| Anemia | 7 (18.4) | 3 (7.9) |
Acknowledgments
We thank the patients who participated in this study and their families, the study investigators, and study staff. This trial was sponsored in part by Phoenix Biotechnology, Inc.
No part of this article may be reproduced, stored, or transmitted in any form or for any means without the prior permission in writing from the copyright holder. For information on purchasing reprints contact Commercialreprints@wiley.com. For permission information contact permissions@wiley.com.
Footnotes
- ClinicalTrials.gov Identifier: NCT02329717
- Sponsor: Phoenix Biotechnology, Inc.
- Principal Investigator: Jordan Berlin
- IRB Approved: Yes
References
- 1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin 2019;69:7–34. [DOI] [PubMed] [Google Scholar]
- 2. Rahib L, Smith BD, Aizenberg R et al. Projecting cancer incidence and deaths to 2030: The unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res 2014;74:2913–2921. [DOI] [PubMed] [Google Scholar]
- 3. Tempero MA. NCCN Guidelines Updates: Pancreatic Cancer. J Natl Compr Canc Netw 2019;17:603–605. [DOI] [PubMed] [Google Scholar]
- 4. American Cancer Society . Cancer Facts & Figures 2020. Atlanta, GA: American Cancer Society, 2020. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. Stenkvist B, Bengtsson E, Eriksson O et al. Cardiac glycosides and breast cancer. Lancet 1979;1:563. [DOI] [PubMed] [Google Scholar]
- 6. Yang P, Menter DG, Cartwright C et al. Oleandrin‐mediated inhibition of human tumor cell proliferation: Importance of Na,K‐ATPase alpha subunits as drug targets. Mol Cancer Ther 2009;8:2319–2328. [DOI] [PubMed] [Google Scholar]
- 7. Newman RA, Kondo Y, Yokoyama T et al. Autophagic cell death of human pancreatic tumor cells mediated by oleandrin, a lipid‐soluble cardiac glycoside. Integr Cancer Ther 2007;6:354–364. [DOI] [PubMed] [Google Scholar]
- 8. Pan Y, Rhea P, Tan L et al. PBI‐05204, a supercritical CO₂ extract of Nerium oleander, inhibits growth of human pancreatic cancer via targeting the PI3K/mTOR pathway. Invest New Drugs 2015;33:271–279. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9. Hong DS, Henary H, Falchook GS et al. First‐in‐human study of PBI‐05204, an oleander‐derived inhibitor of Akt, FGF‐2, Nf‐kappaBeta and p70S6k, in patients with advanced solid tumors. Invest New Drugs 2014;32:1204–1212. [DOI] [PubMed] [Google Scholar]