Panbela Therapeutics : Presentation

SBP-101, a Polyamine Metabolic Inhibitor, Administered in Combination with Gemcitabine and Nab-paclitaxel, shows Signals of Efficacy as

First-Line Treatment for Subjects with Metastatic Pancreatic Ductal Adenocarcinoma	ASCO 2021 Abstract 4127
N. Singhal,1 D. Sigal,2 N.C. Tebbutt,3 A.F. Hezel,4 A. Nagrial,5 S. Lumba,6 T. George,7 S.L. Smith,8 S. Gagnon,9 M.J. Walker,9 M.T. Cullen,9
1Adelaide Cancer Centre, Kurralta Park, SA, and University of Adelaide, SA, Australia; ; 2Scripps Clinic and Scripps MD Anderson Cancer Center, San Diego, CA, USA; 3Olivia Newton-John Cancer, Wellness and Research Centre, Austin Health, Heidelberg, VIC, Australia; 4University of Rochester Medical
Center, Rochester, NY, USA; 5Blacktown Hospital Cancer and Haematology Centre, Blacktown, NSW, Australia; ; 6John Flynn Private Hospital, Tugun, QLD, Australia; 7University of Florida, Gainesville, FL, USA; 8Courante Oncology, Excelsior, MN, USA; 9Panbela Therapeutics, Inc, Minneapolis, MN, USA

Abstract

DemographicsPharmacokinetics

Efficacy Results

Background: SBP-101, a polyamine metabolic inhibitor, inhibited growth in 6 human pancreatic ductal adenocarcinoma (PDA) cell lines and 3 murine xenograft tumor models of human PDA. SBP-101 monotherapy in heavily pre-treated PDA patients (> 2 prior regimens)

			Cohort 4
Cohort 1	Cohort 2	Cohort 3	+	All

	Cohort 1		Cohort 2		Cohort 3
	(0.2 mg/kg)		(0.4 mg/kg)		(0.6 mg/kg)
	(N=4)		(N=7)		(N=5*)

Efficacy results are presented for subjects in Cohort 2, N=7, and Cohort 4 + Phase 1b, N=30. In 11 subjects SBP-101 was suspended to investigate vision AEs; those subjects continued treatment with G and A.

showed a median survival of 5.9 months at the optimal dose level.

Purpose: To assess the PK, safety and efficacy of SBP-101 in combination with gemcitabine (G) and nab-paclitaxel (A) in patients with previously untreated metastatic PDA.

Methods: In a modified 3+3 dose escalation scheme, subcutaneous injections of SBP-101 were dosed at 0.2, 0.4 or 0.6 mg/kg days 1-5 of each 28-day cycle. G (1000 mg/m2) and A (125 mg/m2) were administered intravenously on Days 1, 8, and 15 of each cycle. PK was evaluated on day 1 of cycle 1 in cohorts 1-3. Safety was evaluated by clinical and laboratory assessments. Efficacy was assessed by CA19- 9 levels, objective response using RECIST criteria, progression-free survival (PFS) and overall survival (OS). A 4th cohort using a modified dosing schedule of 0.4 mg/kg SBP-101 days 1-5 for cycles 1-2 and days 1, 8, and 15 every cycle thereafter was added to mitigate hepatic toxicity, and that dose and schedule were recommended for Phase 1b expansion.

Interim Results: Fifty patients were enrolled (N=25, Phase 1a and N=25, Phase 1b) and have received up to 12 treatment cycles. SBP-101 plasma Cmax and AUC0-t increased in a slightly more than dose proportional manner and were unchanged by the addition of G and A. PK parameters of G and A were unaltered by increasing doses of SBP-101. The most common non-serious adverse events related to SBP-101 (>10%) are fatigue (N=15), LFT/transaminase abnormalities (N=15), vision abnormalities (N=6), injection site pain (N=13), dehydration (N=7), diarrhea (N=7) and nausea (N=6). Serious adverse events related to SBP-101 observed in some subjects include hepatic toxicity (N=

6) and retinal toxicity (N=6) both occurring after prolonged treatment and requiring SBP-101 dose reduction or discontinuation. There is no

evidence of SBP-101-related bone marrow suppression or peripheral neuropathy. At the Phase 1b dose and schedule (N=30), CA19-9

levels decreased 60-99% in 19 of 29 evaluable patients, with 12/28 evaluable patients achieving partial responses (43%) and 11/28

achieving stable disease at 8 weeks (39%). Nine subjects are ongoing. PFS was confounded by SBP-101 dosing holds implemented to

investigate potential toxicity. Median OS has not been reached.

							(0.2 mg/kg)(0.4 mg/kg)			(0.6 mg/kg)			Phase 1 b			Cohorts
							(N=4)		(N=7)			(N=9)			(N=30)			(N=50)
		Age (years)
		Mean (SD)					66.8 (9.88)	62.1 (9.55)		65.8 (7.66)			62.6 (9.68)			64.5 (9.21)
		Median					71 (52-73)	65 (42-72)		68 (47-74)		62.5 (37-80)			65 (37-80)
		(Range)

Gender n (%)
Male	2 (50.0%)	4 (57.1%)	5 (55.6%)	22 (73.3%)	33
					(66.0%)
Female	2 (50.0%)	3 (42.9%)	4 (44.4%)	8 (26.7%)	17 (34.0%)
Race n (%)

	White	3 (75.0%)	7 (100.0%)	8 (88.9%)	28 (93.3%)	46 (92.0%)
	Asian		1 (25.0%)	0	1 (11.1%)	2(6.7%)		4 (8.0%)

Table 1. Demographics of the study population. There were no significant differences in gender or age between cohorts. Most of the subjects were White.

		Cmax (µg/mL)
			Mean		0.0266	0.1147	0.1467
			Range		0.0132-0.0416	0.0771-0.167	0.0919-0.195
		T		(hr)
		max
			Mean		0.5	0.5	0.5
	*PK samples were collected for 5 of the 9 patients in Cohort 3.

Table 2. Pharmacokinetics. Pharmacokinetic parameters (PK) for SBP-101 in cohort 1 were below the limits of detection at most time points, but plasma Cmax and Tmax were measurable. Cmax values were similar to the previous Phase 1 monotherapy study (data on file) and Tmax was the same in both studies. SBP- 101 plasma Cmax and AUC0-t increased in a slightly more than dose proportional manner and were unchanged by the addition of G and A. PK parameters of G and A were unaltered by increasing doses of SBP-101(data on file).

A.		Best Tumor Response per Subject
		Cohort 2 N=7
	100%
	90%
	80%
	70%
	60%
	50%
	40%
Baseline	30%		PD
0%
	20%
of	10%
-10%
Percentage	-20%		PR
-60%
	-30%
	-40%
	-50%

-70%-80%-90%-100%

DECEASED LIVING

Figure 1A. Best Tumor Response per Subject - Cohort 2, N=7. Best response in evaluable subjects was PR in 5 (71%) and SD in

1. Best Tumor Response per Subject

Cohort 4 + Phase 1b N=29

	100%
	90%
	80%
	70%
	60%
	50%
	40%
	* *
Baseline	30%	* *								PD
20%
	10%
	*
of	0%
-10%
Percentage						*
-50%
	-20%	*						PR
	-30%	*	* * * * *
	-40%
	-60%							*
							* * *
	-70%
	-80%							*
	-90%
	-100%
							*
				OFF STUDY			ON STUDY	* LIVING

Figure 1B. Best Tumor Response per Subject - Cohort 4 + Phase 1b, N=29. Best response in evaluable subjects was PR in 14 (48%)

Conclusions: Interim results suggest SBP-101 may enhance first-line treatment with G and A in patients with metastatic PDA. Hepatic

toxicity can be mitigated with dose reduction or discontinuation. Retinal toxicity that occurred in some subjects is under investigation.

Safety

2 (29%). Two patients are still in long-term follow up at 23.3+ and 21.5+ months, respectively.

and SD in 10 (34%). One subject did not have a post baseline scan with RECIST tumor assessment.

ASCO 2021 Abstract 4127

ClinicalTrials.gov Identifier: NCT03412799

Introduction

Polyamines (PAs) are aliphatic cations found in nearly all living cells, and they are critical for cell growth, protein synthesis and apoptosis. Although their concentrations are tightly controlled in normal cells, many tumors, including PDA, have elevated PA levels making them a promising therapeutic target. SBP-101, an analogue of the naturally occurring PA, spermine, is a polyamine metabolic inhibitor (PMI) that reduces native PA pools by inhibiting key synthetic enzymes and induction of catabolic enzymes. Non-clinical studies showed SBP-101 to have efficacy against PDA in vitro and in vivo, and a first-in-human monotherapy study in heavily pretreated patients with metastatic PDA (most had ≥2 prior chemotherapy regimens) demonstrated an acceptable safety profile below the MTD. In that study there was no significant bone marrow suppression or peripheral neuropathy as is commonly seen with gemcitabine (G) and nab-paclitaxel (A), suggesting the feasibility of SBP-101 as an addition to combination first-line treatment.

Study Design

The Safety Population includes all subjects who received at least one dose of SBP-101 (N=50). Related adverse events (AEs) were defined as definitely, probably or possibly related and not related events as unlikely or not related. In the total N, subjects are counted only once at the highest grade for each event.

			Grade		Grade	Grade		Grade	Grade		Total
	Event		1		2	3		4	5		N (%)
	Fatigue	8	5	2	0	0	15 (30%)
	Elevated Liver Function Tests	1	0	12	1	1*	15 (30%)
	Injection site pain	11	2	0	0	0	13 (26%)

Vision events	**	0	4	6	0	0	10 (20%)

Dehydration	1	4	2	0	0	7 (14%)
Diarrhea	2	3	1	0	0	6 (12%)
Nausea		3	2	1	0	0	6 (12%)

*Patient exceeded the maximum tolerated dose and schedule.

**includes blurred vision, visual impairment, visual acuity reduced and retinopathy.

Table 3A. SBP-101-related adverse events occurring in ≥5 subjects (10%), N=50.

Event	SBP-101	G+A		All 3	Total N (%)
Neutropenia	0	19 (1G, 18	G+A)	1	20 (40%)

Elevated LFTs	5		0	9	14 (28%)
Anemia	0		7 (G+A)	0	7 (14%)
Diarrhea	0		6 (3A, 3 G+A)	1	7 (14%)
Fatigue	0		4 (G+A)	2	6 (12%)
Vision events	3		1 (G)	2	6 (12%)
Dehydration	2		2 (1A, 1 G+A)	0	4 (8%)
Peripheral neuropathy	0		3 (A)	0	3 (6%)

Table 3C. Grade ≥3 adverse events attributable to any study medication, N=50. The most common Grade ≥3 AEs related to any study medication were neutropenia in 20 subjects (19 attributed to G+A and 1 attributed to all 3) and elevated liver function tests in 15 subjects (5 attributed to SBP-101and 10 attributed to all 3). SBP-101-relatedincreases in LFTs were asymptomatic in all but 2 subjects and reversed in all but one subject when SBP-101administration was interrupted and dose-reducedor discontinued. Six subjects experienced vision adverse events (3 possibly related to SBP-101,1 related to gemcitabine and 2 related to all 3 based on PI assessment. All are considered by the sponsor to be possibly related to SBP-101);5 had findings consistent with retinopathy.

A statistical correlation analysis suggested an association with high cumulative doses of corticosteroids, total cumulative dose and duration of treatment, prior history of eye

C.		Best CA 19-9 percent change from Baseline by Response
		Cohort 4 + Phase 1b
-9	≥100%
80%
CA19
60%
in
Baseline	40%
20%
from
0%
Change
-20%
-40%
Percent
-60%
	-80%

-100%

PR SD PD ND

Figure 1C. Best CA 19-9 percent change from Baseline by Response - Cohort 4 + Phase 1b, N=30. Twenty-onesubjects in Cohorts 4 + Phase 1b (70%) had a CA 19-9maximum decrease

greater than 60%.	SD=2	SD=2	SD=4

In the response-evaluable subjects in Cohort 4 + Phase 1b (N=29), 11 had treatment with SBP-101 interrupted to evaluate retinal toxicity; this may confound final efficacy results. In Cohort 2 (N=7) the objective response rate (ORR) was 71%, and the DCR was 100% by RECIST criteria (SD or better for ≥ 16 weeks). Median PFS in Cohort 2 was 5.63 mo and median OS was 10.3 mo compared with ORR of 48%, DCR of 70%, PFS of

5.2 mo and median OS (not yet reached) in Cohort 4 + 1b.

This is a multicenter, open label, Phase 1a/1b study to evaluate to evaluate the safety, tolerability, pharmacokinetics and efficacy of SBP-101 when administered in combination with G and A as first-line therapy in pancreatic cancer patients previously untreated for metastatic disease. The objective was to determine a recommended Phase 2 dose. Using a modified 3+3 dose escalation scheme, cohorts of subjects were dosed with subcutaneous injections of SBP-101 at 0.2, 0.4 or 0.6 mg/kg days 1-5 of each 28-day cycle. G (1000 mg/m2) and A (125 mg/m2) were administered intravenously on Days 1, 8, and 15 of each cycle. PK was evaluated on day 1 of cycle 1 in cohorts 1-3. Subjects were to be treated until disease progression or the development of dose-limiting toxicity. Safety was evaluated by clinical and laboratory assessments. Efficacy was assessed by objective response using RECIST criteria and CA19-9 level. The protocol was amended to evaluate progression-free survival (PFS) and overall survival (OS) beginning with patients in Cohort 2. A 4th cohort using a modified dosing schedule of 0.4 mg/kg SBP-101 days 1-5 for cycles 1-2 and days 1, 8, and 15 every cycle thereafter was also added to mitigate hepatic toxicity, and that dose and schedule were evaluated in Phase 1b expansion. Enrolment was completed after 25 subjects were enrolled in Phase 1b. Safety and efficacy results of Cohort 2 vs Cohort 4 + Phase 1b subjects were compared for presentation.

Grade ≥3 AEs of Special Interest	N	%				G+A %*
Hematologic Events
Neutropenia	20	40%				38%
Leukopenia	0	-				31%
Anemia	9	18%				13%
Thrombocytopenia	1	2%				17%
Non-hematologic Events
Peripheral Neuropathy	3	6%				17%
Fatigue	6	12%				17%
Diarrhea	6	12%				6%

*Historical control data, MPACT study G+A arm, N=431 Source: Von Hoff NEJM 2013

Table 3B. Grade ≥3 adverse events of special interest compared to historical data on G+A.

disorders and prior treatment for a different malignancy.

The addition of SBP-101 to the treatment regimen did not

result in any substantial changes in the frequency of Grade ≥

3 hematologic events, peripheral neuropathy, fatigue or diarrhea when compared with historical control data on G+A combination therapy. Liver toxicity seen early in the study was successfully mitigated by dose reduction. Retinopathy

• Grade 3 occurred in 10% of patients, possibly related to
  SBP-101. The natural history and potential mitigation of retinopathy will be evaluated in a randomized controlled clinical trial.

Conclusions

Conclusions: SBP-101was well-toleratedwhen administered at doses and schedules tested in combination with G+A in subjects with previously untreated metastatic pancreatic adenocarcinoma. Treatment-relatedliver function abnormalities seen early in the study were successfully mitigated with SBP-101dose reduction in Phase 1b. There was no evidence that SBP-101potentiates the Grade ≥3 hematologic events or peripheral neuropathy typically seen with G+A alone. Vision AEs in some subjects, not observed in earlier studies, will require baseline and periodic ophthalmology examinations in future studies. Overall ORR (48%) and DCR (70%) exceeded the historical rates reported for G+A* (23%, 48%) and FOLFIRINOX** (32%, 70%) in pivotal trials; radiologic responses were accompanied by large decreases in CA19-9levels. Optimal dosing regimens have been explored and signals of efficacy support continued development of SBP-101as an addition to first-linetreatment for advanced PDA and as neo- adjuvant treatment for patients with potentially resectable disease.

Sources: *Von Hoff NEJM 2013, **Conroy NEJM 2011