Trial of NanoPac® in Subjects With Locally Advanced Pancreatic Adenocarcinoma

In this open-label, dose-escalating, Phase IIa trial, subjects with locally advanced pancreatic adenocarcinoma will receive intratumoral (ITU) NanoPac® (Sterile Nanoparticulate Paclitaxel) via endoscopic ultrasound-guided direct injection.

Subjects will be enrolled in sequential cohorts of NanoPac® at escalating doses, at a volume based on up to 20% of calculated tumor volume (with a maximum injection volume of 5 mL per subject). During the first phase of the trial (dose escalation), each cohort will have three subjects, with cohorts enrolled sequentially starting at the lowest concentration. Following DSMB review of the cohort data, the next cohort may begin enrolling, an additional three subjects at the current dose may be enrolled, or if the first dose does not provide adequate safety and tolerability the study may be halted.

The dose determined to be most suitable for further evaluation, defined as the highest dose with an acceptable safety and tolerability profile as determined by the Data Safety Monitoring Board (DSMB), will be the dose used in the second phase of the study which will enroll 22 additional subjects who will receive two injections of NanoPac® at the same dose one month apart. In the third phase of the study, up to 30 subjects will receive up to four injections of NanoPac at the same dose, one month apart.

Plasma samples will be taken at various time points on the day of NanoPac® injection as well as once at each of the study visits, to characterize the pharmacokinetics (PK) of ITU NanoPac®.

Subjects will be followed for 12 months after NanoPac® injection for safety, overall survival (OS), progression-free survival (PFS), CA-19-9 levels, carcinoembryonic antigen (CEA) levels, reduction in pain, and tumor response to therapy (as shown by imaging).

• NanoPac® (Drug), also known as Paclitaxel: Subjects with locally advanced pancreatic adenocarcinoma will receive intratumoral (ITU) NanoPac® (Sterile Nanoparticulate Paclitaxel) via endoscopic ultrasound-guided direct injection.

Primary outcomes

• Number of Subjects With Treatment Emergent Adverse Events (Safety and Tolerability) [Up to Week 24 for Dose Escalation subjects; up to Week 28 for Second Phase subjects; up to 9 Months for Third Phase subjects.]: Treatment Emergent Adverse Events will include laboratory assessments, physical examination findings, and vital signs.

Secondary outcomes

• Target Tumor Assessment [Week 24]: Response was determined using RECIST 1.1 parameters (complete response, partial response, stable disease, progressive disease, unevaluable) for the treated lesion in all groups.
• Plasma Paclitaxel Concentration (pg/mL) [Day 1 and Week 24]: Plasma paclitaxel concentrations were analyzed in the dose escalation phase on Day 1 prior to injection and at 1, 2, 4, 6, and 24 hours after NanoPac injection, as well as at all other study visits. In the second and third phases, plasma paclitaxel concentrations were analyzed on Day 1 prior to NanoPac injection, and at 1 and 2 hours post NanoPac injection on all injection occasions, and at all study visits.
• Pain (Visual Analog Scale) Score [Day 1 (pre-injection) and Week 24]: The visual analog scale (VAS) ranks pain from numbers 0 (no pain) to 10 (most pain). Lower scores mean a better outcome.
• Serum CA19-9 Level [Day 1 (Pre-Injection) and Week 24]: CA19-9 is a tumor marker for pancreatic cancer. Serum CA19-9 levels were assessed at all study visits.
• Serum CEA Levels [Day 1 (Pre-Injection) and Week 24]: Carcinoembryonic antigen (CEA) is a tumor marker for pancreatic cancer.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Signed informed consent;
* Age ≥18 years;
* Histologically/cytologically confirmed locally advanced pancreatic adenocarcinoma; at least one lesion with a diameter of at least 1.5 cm but no more than 6 cm as documented via imaging (within 6 weeks of Screening);
* Subject not a candidate for surgery;
* Completion of at least one standard of care IV chemotherapy course for subjects in the dose escalation phase of the study. IV chemotherapy will be initiated prior to first NanoPac injection for subjects in the second and third phases. Hematologic recovery must be confirmed prior to study entry;
* Performance Status (ECOG) 0-1 at study entry;
* Life expectancy of at least 3 months;
* Adequate marrow, liver, and renal function at study entry:

  * ANC ≥ 1.5 x 109/L
  * Hemoglobin ≥ 9.5 grams/dL
  * Platelets ≥ 75 x 109/L
  * Total bilirubin ≤ 1.5x institutional ULN
  * AST/ ALT ≤ 2.5x institutional ULN
  * Creatinine ≤ 1.5x institutional ULN
* Effective contraception if the risk of conception exists.

Exclusion Criteria:

* Thrombotic or embolic events;
* Acute or subacute intestinal occlusion;
* History of inflammatory bowel disease;
* Known hypersensitivity to study drugs;
* Known drug or alcohol abuse;
* Pregnant or breastfeeding women;
* Previous or concurrent history of non-pancreatic malignancy except for non-melanoma skin cancer.

Participant flow

Outcome results

• Number of Subjects With Treatment Emergent Adverse Events (Safety and Tolerability) (Primary), Count of participants, Participants: Dose Escalation: NanoPac® 6 mg/mL 3; Dose Escalation: NanoPac® 10 mg/mL 3; Dose Escalation: NanoPac® 15 mg/mL 4; Second Phase: NanoPac® 15 mg/mL 23; Third Phase: NanoPac® 15 mg/mL 19
• Target Tumor Assessment (Secondary), Count of participants, Participants: Dose Escalation: NanoPac® 6 mg/mL 0; Dose Escalation: NanoPac® 10 mg/mL 0; Dose Escalation: NanoPac® 15 mg/mL 0; Second Phase: NanoPac® 15 mg/mL 0; Third Phase: NanoPac® 15 mg/mL 0
• Plasma Paclitaxel Concentration (pg/mL) (Secondary), Mean, pg/mL: Dose Escalation: NanoPac® 6 mg/mL 62.1 +/- NA; Dose Escalation: NanoPac® 10 mg/mL ; Dose Escalation: NanoPac® 15 mg/mL 304 +/- NA; Second Phase: NanoPac® 15 mg/mL 5497.0 +/- 11887.04; Third Phase: NanoPac® 15 mg/mL 17347.7 +/- 27686.44
• Pain (Visual Analog Scale) Score (Secondary), Mean, units on a scale: Dose Escalation: NanoPac® 6 mg/mL 0 +/- 0; Dose Escalation: NanoPac® 10 mg/mL 0 +/- 0; Dose Escalation: NanoPac® 15 mg/mL 5.5 +/- 4.12; Second Phase: NanoPac® 15 mg/mL 1.2 +/- 2.41; Third Phase: NanoPac® 15 mg/mL 0.8 +/- 1.42
• Serum CA19-9 Level (Secondary), Mean, U/mL: Dose Escalation: NanoPac® 6 mg/mL 248 +/- NA; Dose Escalation: NanoPac® 10 mg/mL 24 +/- 24; Dose Escalation: NanoPac® 15 mg/mL 2958 +/- 4749; Second Phase: NanoPac® 15 mg/mL 952 +/- 2171; Third Phase: NanoPac® 15 mg/mL 198 +/- 362
• Serum CEA Levels (Secondary), Mean, ug/L: Dose Escalation: NanoPac® 6 mg/mL 1.65 +/- 0.778; Dose Escalation: NanoPac® 10 mg/mL 27.1 +/- 41.57; Dose Escalation: NanoPac® 15 mg/mL 4.58 +/- 1.68; Second Phase: NanoPac® 15 mg/mL 5.17 +/- 3.163; Third Phase: NanoPac® 15 mg/mL 6.69 +/- 5.976

Adverse events

Time frame: Up to 9 months

Serious adverse events by term

Other adverse events by term

87 more terms not shown.

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• Results publication: Sharma NR, Lo SK, Hendifar A, Othman MO, Patel K, Mendoza-Ladd A, Verco S, Maulhardt HA, Verco J, Wendt A, Marin A, Schmidt CM, diZerega G. Response of Locally Advanced Pancreatic Cancer to Intratumoral Injection of Large Surface Area Microparticle Paclitaxel: Initial Report of Safety and Clinical Outcome. Pancreas. 2023 Mar 1;52(3):e179-e187. doi: 10.1097/MPA.0000000000002236. PMID 37782888

• Study Protocol (PDF, 2020-03-25)
• Statistical Analysis Plan (PDF, 2023-04-03)

• Shelagh Verco, PhD, Study director, Vice President, Clinical Development, NanOlogy, LLC