Feasibility of SM-88 in Pancreatic Cancer After Multiple Prior Lines and ECOG ≤ 2

 Pancreatic cancer remains a clinically challenging disease with an 80% mortality rate within 12 months of initial diagnosis (ACS Estimates). Recent clinical trials have shown median overall survival of four to six months with single digit response rates in the second-line setting. (Conroy et al. 2011, Wang-Gillam 20161,2)

 The standard of care remains highly toxic chemotherapy regimens (FOLFIRINOX or gemcitabine with nab-paclitaxel) with grade 3 or greater toxicity in over 50% of patients.

 Currently, there are no FDA approved treatments specifically indicated for third-line metastatic pancreatic adenocarcinoma patients. Neither ASCO nor NCCN guidelines recommend any treatment for third-line pancreatic cancer patients who may also be excluded from clinical trials based on performance status and residual toxicity.

 SM-88 is a novel anti-cancer regimen that consists of one investigational agent (D,L-alpha-metyrosine {D/L}), and three re-purposed drugs (methoxsalen, phenytoin, and sirolimus).

 It is hypothesized that all four, including both isomers of D/L contribute to the anti-cancer properties of SM-88 and are believed to be distinct drugs with independent mechanisms of action.

 The high specificity of D/L for cancer cells, and the low doses of the repurposed agents, may contribute to a favorable toxicity profile in this especially susceptible population.

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

BACKGROUND RESULTS

TRIAL DESIGN

METHODS

 Tyme-88-Panc (NCT#03512756) is a 2 Part randomized, open-label Phase II of SM-88 in metastatic progressive disease PDAC after at least 1 prior line of chemotherapy, ECOG score ≤ 2 and as little as 2 weeks from prior systemic therapy.

 In Part 1, subjects were randomized to receive one of two D/L oral dosing regimens, 230 mg BID, or 460 mg BID.  All subjects also received oral methoxsalen (10 mg QD), phenytoin (50 mg QD), and sirolimus (0.5 mg QD),

regardless of randomization.  The present study describes the safety analysis from the randomized Part 1 of Tyme-88-Panc. Preliminary efficacy results (poster board A16) and PK data (poster board B15) are presented in elsewhere.

Table 1: Demographics and Baseline Characteristics

 Prospective Phase II cohort. The severity of adverse events (AE) was graded using Common Terminology Criteria for Adverse Events (CTCAE),

version 4.03. The AE reporting period was from the time of signing the informed consent until 28 days after the last dose of SM-88.

REFERENCES1. FOLFIRINOX versus Gemcitabine for Metastatic Pancreatic Cancer. Conroy et al., NEJM, 2011

364 (19).2. Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after

previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial. Wang-Gillam et al. Lancet, 2016

ENROLLMENT & EVALUABLE SUBJECTS

Grade

UnrelatedBefore

Starting SM-88

Unrelated On SM-88

Possibly Related

ProbablyRelated Related

1 0 0 0 0 02 3 4 0 0 03 9 17 1 0 04 2 3 0 0 15 5 4 0 0 0

Unknown 0 1 0 0 0Total 19 29 1 0 1

HYPOTHESISWe sought to determine the feasibility of a trial in >3L PDAC using the ongoing Tyme-88-Panc trial (NCT#03512756) and comparing outcomes limiting participation by prior lines and other risk factors.

230 mg BIDN = 17*

460 mg BIDN = 19

TotalN = 36

All TEAEs 15 (88.2) 17 (89.5) 32 (88.9)Abdominal pain 7 (41.2) 11 (57.9) 18 (50.0)

Dyspnea 5 (29.4) 3 (15.8) 8 (22.2)

Fatigue 5 (29.4) 3 (15.8) 8 (22.2)

Constipation 3 (17.6) 4 (21.1) 7 (19.4)

Decreased Appetite 3 (17.6) 4 (21.1) 7 (19.4)

Back pain 4 (23.5) 2 (10.5) 6 (16.7)

Diarrhea 3 (17.6) 3 (15.8) 6 (16.7)

Bacteremia 3 (17.6) 2 (10.5) 5 (13.9)

Headache 2 (11.8) 2 (10.5) 4 (11.1)

Arthralgia 2 (11.8) 2 (10.5) 4 (11.1)

Dehydration 2 (11.8) 2 (10.5) 4 (11.1)

Nausea 1 (5.9) 3 (15.8) 4 (11.1)

Grade 3-4 TEAEs with 1 Prior Line 1 1 2

Grade 3-4 TEAEs with 2 Prior Lines 4 3 7

Grade 3-4 TEAEs with >3 Prior Lines 4 6 10

Marcus S Noel1, Andrea Wang-Gillam2, Allyson J Ocean3, Giuseppe Del Priore4, Vincent J Picozzi51University of Rochester Wilmot Cancer Institute, Rochester, NY; 2Washington University, St. Louis, MO; 3Cornell Medical College, NY, NY; 4Tyme Technologies, Inc., NY, NY; 5Virginia Mason Medical Center, Seattle, WA

 85 subjects were consented for screening and 38 met criteria for randomization.  10 subjects did not complete at least one Cycle of SM-88 treatment (median 17 days; range 7 – 26 days total

treatment), and were excluded from subsequent efficacy analyses per protocol. Â The present analysis includes data from all 38 randomized subjects.

Age, years ± SD 66.7 ± 11.0

Sex, n (% female) 16 (42.1%)

Weight, kg ± SD 70.2 ± 14.6

Body Mass Index, BMI ± SD 24.2 ± 4.7

Race, n (%)

White 36 (94.7%)

Black or African American 1 (2.6%)

Asian 1 (2.6%)

Stage at Diagnosis1 1 (2.6%)

2 10 (26.3%)

3 10 (26.3%)

4 14 (36.8%)

Unknown 3 (7.9%)

Prior Radiotherapy, n (%) 9 (23.7%)

Prior Surgery, n (%) 12 (31.6%)

Prior Lines of Therapy, n (%)

1 6 (15.8%)

2 17 (44.7%)

3 7 (18.4%)

4+ 6 (15.8%)

Unknown 2 (5.3%)

Prior Therapy Type, (%)

Gemcitabine 84.2%

Fluorouracil 81.6%

Irinotecan 68.4%

Platinum 68.4%

Immunotherapy 10.5%

Investigational agents 10.5%

PARP inhibitors 2.6%

Albumin, g/dL ± SD 3.84 ± 0.43

CA-19.9, IU/mL (median, range) 3,291 (1.2 – 700,000)

Alkaline Phosphatase, U/L ± SD 188 ± 154

Table 2: Overall Number of Subjects with Treatment Experiencing Treatment Emergent Adverse Events (TEAE) (Occurring in at Least 10% of Subjects)

Summary of Serious Adverse EventsTiming Severity*

G2/3 G4 G5 TotalPrior to Dosing 14 2 5 21

On Trial 22 4 4 30Unrelated 21 3 4 28

Possibly Related 1 1 - 2

* Based on CTCAE guidelines: G2 = moderate; G3 = severe; G4 = life threatening; G5 = death

 Thirty-two (84.2%) of subjects experienced a TEAE, with 15 (39.5%) of subjects experiencing a TEAE related to SM-88.

 16.2% of adverse events were considered at least possibly related to SM-88.

 No dose dependent increases in TEAEs were observed. One subject treated with 460mg BID experienced 2 AEs

considered to be dose limiting toxicities, rash and arthralgia. AEs were successfully managed and this subject resumed treatment with SM-88.

Table 3: Summary of Severe Adverse Events (SAE), by Grade and Relationship

 There was 1 SAE (rash) considered possibly related to SM-88, and 1 SAE (hypotension) considered to be related to SM-88.

 The only subject who experienced a drug related SAE, remains on treatment.

 3 subjects discontinued SM-88 due to an AE. 5/40 (12.5%) subjects who were screened but not randomized in

2018, died after consent but before receiving SM-88. No deaths were related to SM-88.

Figure 1: SAEs by Cycle

Figure 2: EORTC Questionnaire Global Assessment of Health and Quality of Life (QOL)

0

1

2

3

4

5

6

SCR C1D1 C2D1 C3D1 C4D1 EOT28DFU

Health QLQ-C30 Question 29

0

1

2

3

4

5

6

SCR C1D1 C2D1 C3D1 C4D1 EOT28DFU

Quality of Life QLQ-C30 Question 30

There was no significant difference by dose level in either EORTC question. On average, patients maintained similar QOL and global health while receiving SM-88. Both scores declined after stopping SM-88.

Table 4: Grade 3, 4, and 5 AEs by Risk Factors, Dose Level, and Prior Lines of Chemotherapy (number of subjects)

230 mg BIDN = 19

460 mg BIDN = 19

TotalN = 38

All 9 (47.4) 10 (52.6) 19 (50.0)By Prior Lines1 Prior Line 1 1 22 Prior Lines 4 3 7> 3 Prior Lines 4 6 10Age > Median1 Prior Line 1 1 22 Prior Lines 2 2 4> 3 Prior Lines 2 2 4Female1 Prior Line 0 1 12 Prior Lines 1 2 3> 3 Prior Lines 1 3 4BMI < Median1 Prior Line 0 0 02 Prior Lines 2 1 3> 3 Prior Lines 2 5 7Albumin < Median1 Prior Line 1 1 22 Prior Lines 3 2 5> 3 Prior Lines 2 3 5CA-19.9 > Median1 Prior Line 0 0 02 Prior Lines 1 2 3> 3 Prior Lines 3 3 6Prior Radiotherapy1 Prior Line 0 0 02 Prior Lines 1 0 1> 3 Prior Lines 0 3 3

CONCLUSIONSÂ On currently approved therapies for PDAC, approximately 50% of patients may experience

SAEs and almost all patients may experience AEs. In a prospective Phase II trial studying SM-88 in refractory PDAC, only 2 Possibly Related SAEs

were reported. These 2 SAEs occurred in 1 subject. AEs were not increased after stratifying several common risk factors across both doses of SM-

88 studied. In a heavily pre-treated pancreatic cancer subject population with extensive co-morbidities, SM-

88 was well-tolerated. In this preliminary unplanned analysis of AEs by prior lines of treatment and dose level of SM-

88, AEs were not increased in either dose level after any number of prior lines of therapy. Study data confirms the feasibility of treating subjects with ≥3rd line PDAC with SM-88. Subjects on SM-88 did not experience an unacceptable level of treatment related SAEs.

0.0%

10.0%

20.0%

30.0%

40.0%

50.0%

60.0%

Pre-Randomzation(n = 36)

Cycle 1(n = 38)

Cycle 2(n = 28)

Cycle 3(n = 14)

Cycle 4(n = 11)

Percentage of Subjects Experiencing an SAE by Cycle

Grade 2 Grade 3/4 Grade 5

* Two subjects did not have data available at the time of this analysis.