Evaluating Non-hormonal Therapy in a Phase II Trial of SM-88for Rising PSA Prostate Cancer

 Treatment options for recurrent non-metastatic prostate cancer (nmPC) generally include toxic systemic treatments, such as androgen deprivation therapy (ADT), with an uncertain impact on clinical benefits.

 The most widely used biomarker for clinical benefit in prostate cancer patients is prostate specific antigen (PSA).

 While hormone therapy often leads to a rapid decline in PSA, non-hormonal therapies may exhibit a reduced or no effect on absolute PSA levels.

 Emerging biomarkers, such as circulating tumor cells (CTC), may be informative of clinical benefit following treatment with non-hormonal therapies.

 SM-88 is an oral non-hormonal investigational agent (D,L-alpha-metyrosine) used with methoxsalen, phenytoin, and sirolimus (SM-88 Therapy).

 It is hypothesized that methoxsalen, phenytoin, and sirolimus enhance the anti-cancer properties of both the D- and L- isomers of SM-88. Both the D-and L- isomers are believed to be distinct drugs with independent mechanisms of action.

Corresponding Author:(e): Giuseppe.DelPriore@TymeInc.com (ph): +1-917-634-6165

INTRODUCTION

OBJECTIVES

RESULTS

CONCLUSIONS

Benjamin Adam Gartrell1, Giuseppe Del Priore2,3, Avi S. Retter4, Wen-Tien Chen5, Gerald H. Sokol6, Alexander G. Vandell2, Mack Roach III7; 1Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY; 2Tyme Inc, New York, NY; 3Morehouse School of Medicine, Atlanta, GA; 4New York Cancer and Blood Specialists, Bronx, New York;5Renaissance School of Medicine at Stony Brook University, Stony Brook, NY; 6Florida Cancer Specialists and Research Institute, Hudson, FL; 7University of California San Francisco, San Francisco, CA

Table 1. Demographics and Baseline Characteristics

N=23

Age, mean ± SD 70.6 ± 7.4

Weight (kg), mean ± SD 87.4 ± 15.7

BMI, mean ± SD 28.9 ± 4.5

Race, n (%)

White 16 (69.6%)

Black 5 (21.7%)

Other 2 (8.7%)

Prior Surgery, n (%) 7 (30.4%)

Prior Radiotherapy, n (%) 14 (60.9%)

Previous Androgen Deprivation Therapy, n (%) 17 (73.9%)

Current Androgen Deprivation Therapy, n (%) 1 (4.3%)

PSA (ng/mL), median (range) 6.4 (1.7 – 80.1)

PSA Doubling Time (months), median (range) 6.2 (1.4 – 37.6)

ECOG Performance Status Score, median (range) 0 (0 – 1)

Gleason Score, median (range) 7 (6 – 10)

Concomitant Disease States, n (%)

Coronary Artery Disease 3 (13.0%)

Diabetes 4 (17.4%)

Hypertension 15 (65.2%)

TRIAL DESIGN

REFERENCES

 Tyme2016b (NCT02796898) is a Phase 1b/2, open-label, dose escalation study to evaluate SM-88 in subjects with recurrent non-metastatic prostate cancer.

 Subjects must be males ≥18 years of age, with an ECOG score ≤ 1, PSA ≥ 1 ng/mL, no radiographically detectable lesions, and rising PSA according to Prostate Cancer Working Group 3 (PCWG3) criteria.

 All subjects in phase 2 received 230 mg BID of SM-88 orally. Subjects also received oral doses of methoxsalen (10 mg), phenytoin (50 mg), and sirolimus (0.5 mg) once per day.

 The present study provides an update on the safety and efficacy of SM-88 Therapy in subjects with non-metastatic prostate cancer.

 PFS was defined as either PSA progression, local progression, metastatic disease, or death.

 To evaluate the use of the SM-88 Therapy before hormone therapy in high-risk biomarker recurrent prostate cancer subjects.

 Preliminary assessment on the efficacy and safety of the SM-88 Therapy in a chronic use maintenance setting.

 Comparison of circulating tumor cell (CTC) and PSA biomarkers in relation to prostate cancer progression.

Figure 1: Circulating Tumor Cell Response

 All subjects had detectable CTCs at baseline.

 After 3 cycles of therapy (12 weeks), there was a 65.3% (range -100% to -8.8%) median CTC decrease from baseline (n=18), with all subjects having CTC counts below baseline.

 For subjects who received >3 cycles of the SM-88 Therapy, CTCs generally continued to decrease and remained below baseline for the duration of the SM-88 Therapy.

 Median baseline CTC (per 4 ml) for subjects with radiographic progression (n=3) was 122 cells vs 40 for subjects with no radiographic progression (p<0.003).

Figure 2: PSA Response PSA levels generally remained stable during

treatment. After 3 cycles of therapy (12 weeks), median PSA increased 40.2% from 6.4 to 9.0.

 PSA Doubling Time improved 34.4% from 6.1 months to 8.2 months for all subjects completing 3 cycles of therapy (n=20).

 52% (12/23) of subjects experienced an improvement in PSA Doubling Time.

 Median baseline PSA for subjects with radiographic progression was 13.4 versus 5.6 for for subjects with no radiographic progression.

 PSA progressions have not yet been adjudicated.

Figure 3: Radiographic Progression Free Survival

 No subject developed metastatic disease (mPFS = 100%, median duration of therapy 6.5 (2.6 – 14.0) months). 7 subjects are still on study. 14 subjects completed 6 or more cycles of therapy.

 SM-88 patients did not develop metastatic disease. As presented elsewhere, a preliminary analysis showed SM-88 did not cause typical ADT-related side effects.

 A full analysis of quality of life is presented on E3 poster: Typical hormone deprivation side effects compared to SM-88 therapy for rising PSA.

 Effects on PSA Doubling Time and CTCs were demonstrated.

DISCUSSIONÂ These preliminary results may suggest a clinically relevant duration of a prolongation of the castrate free

interval in prostate cancer patients with rising PSA. SM-88 may be useful either before or as an additive to current prostate cancer treatments where sparing

testosterone is preferred. Â Ultimately, CTC reduction may be a better surrogate for benefit than PSA, particularly for SM-88 and other

non-hormonal agents. A randomized phase 3 trial is needed to confirm these benefits and may now be warranted.

Figure 4: Radiographic PFS by Subject

Table 2. Reported Adverse Event by Causality

UNRELATED POSSIBLY RELATED PROBABLY RELATED

Total Number of Subjects Experiencing an AE 7 (30.4%) 11 (47.8%) 1 (4.3%)

Total Number of AEs 17 151 31

Grade 1 10 142 32

Grade 2 6 13 0

Grade 3 14 0 0

Grade 4 0 0 0

1) Phase II trial of SM 88 in non-metastatic biochemical recurrent prostate cancer. Roach et al. J Clin Oncol 36, 2018 (suppl 6S; abstr 175).

2) Phase II Trial of SM-88 in Patients with Metastatic Pancreatic Cancer: Preliminary Results of the 1st Stage. Noel et al. J Clin Oncol 37, 2019 (suppl 4; abstr 200).

3) Feasibility of SM-88 in PC After Multiple Prior Lines and ECOG ≤2 (NCT03512756). Noel et al. J Clin Oncol 37, 2019 (suppl 4; abstr 310).

4) Phase II Pharmacokinetics of Oral SM-88 in Heavily Pretreated Advanced Pancreatic Ductal Adenocarcinoma (PC). Noel et al. J Clin Oncol 37, 2019 (suppl 4; abstr 277).

 As of January 2019, 34 subjects were screened, 23 subjects were enrolled and had received SM-88 Therapy, and of those, 21 subjects remained on study for ≥ 12 weeks.

 Only 1 subject reported bisphosphonate use.

Radiographic Progression-

Free

Non-Metastatic

Radiographic Progression

 In total 15/23 (65.2%) subjects reported experiencing an AE.

 The SM-88 Therapy was well tolerated in all subjects. There were no treatment-related serious adverse events. No adverse events resulted in dose delay, discontinuation, or reduction.

 None of the study subjects reported seizures, Posterior Reversible Encephalopathy Syndrome (PRES), hypersensitivity reactions, ischemic heart disease, falls, or fractures.

 The cumulative exposure of the entire cohort was 149 months of daily dosing.118/35 (51.4%) AEs were deemed at least possibly related to the SM-88 Therapy.2The majority of Grade 1 AEs possibly or probably related to the SM-88 Therapy were gastrointestinal in nature, including intestinal bloating, diarrhea, flatulence, loose stool, and nausea3The single Grade 2 AE possibly related to the SM-88 Therapy was fatigue.4The single unrelated Grade 3 AE was hyperkalemia in a subject taking a K+ sparing antihypertensive.

Radiographic Progression-

Free

Non-Metastatic

Radiographic Progression

Radiographic Progression-

Free

Non-Metastatic

Radiographic Progression