Trial of NanoPac® Focal Therapy in Subjects With Prostate Cancer

In this open-label, dose rising, Phase IIa trial with an expanded cohort at the dose of NanoPac® determined to have the best tolerability and safety profile, subjects with prostate cancer scheduled for prostatectomy will have NanoPac® injected under image guidance directly into the lobe of the prostate with the dominant lesion 4 weeks prior to prostatectomy. The study will include a dose escalation phase and a dose confirmation phase.

In the dose escalation phase, NanoPac® concentrations of 6, 10, and 15 mg/mL in an injection volume of 20% of the lobe of the prostate containing the dominant lesion will be studied in cohorts of 3, with cohorts enrolled sequentially starting at the lowest concentration. Following DSMB review of the cohort data the next cohort may begin enrolling, or an additional 3 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 the most suitable for further evaluation, defined as the highest dose with an acceptable safety and tolerability profile as determined by the DSMB, will enroll additional subjects to provide a cohort of 12 subjects at that dose level.

Tumor volume and serum prostate-specific antigen (PSA) will be determined prior to NanoPac® injection. Pharmacokinetic samples, PSA, and ejaculate will be collected in the interval between injection and prostatectomy. Imaging with mpMRI will be performed prior to NanoPac® injection and prior to prostatectomy. Prostate and pelvic lymph nodes excised at prostatectomy will be evaluated.

• NanoPac® (Drug), also known as Paclitaxel: Subjects with prostate cancer scheduled for prostatectomy will have NanoPac® injected intratumorally under image guidance directly into the lobe of the prostate with the dominant lesion 4 weeks prior to prostatectomy.

Primary outcomes

• Number of Participants With Treatment Emergent Adverse Events (Safety and Tolerability) [Day 1 to Day 29]: Treatment Emergent Adverse Events included laboratory assessments, physical examination findings, and vital signs.

Secondary outcomes

• Tumor Response Based on Change in Image Volume on mpMRI [Up to three months prior to consent and Day 29]: Tumor response to treatment with NanoPac was determined by evaluating the change in image volume with multiparametric MRI (mpMRI) within three months prior to consent and again within 48 hours of the prostatectomy procedure (Day 29). In those cases where two dimensions/axes were available, width was imputed to height for the purposes of calculation, i.e. the lesion was assumed to be an oblate spheroid. In those cases where only one dimension/axis was available, that dimension/axis was imputed for all three dimensions i.e. the lesion was assumed to be a sphere. For this reason, analyses were performed for all subjects with two dimensions available, as well as those for which at least one dimension was available. The data presented for this outcome measure is the one dimension lesion volume calculation: Lesion Volume (cc) = (3.14/6)*(length)³, where length is the longer or only measured dimension.
• Tumor Response Based on Histologic Evaluation of Biopsied Prostate Samples (Gleason Score) [Screening and Day 29]: Prostate tissue samples were obtained via biopsy at baseline and immediately prior to prostatectomy (Day 29). Histologic evaluation of these samples was used to determine the Gleason score, and the results at baseline and Day 29 were used to evaluate the tumor response to treatment with NanoPac®. The Gleason score is calculated by adding together the two grades of cancer cells that make up the largest areas of the biopsied tissue sample. The Gleason score usually ranges from 6 to 10. The lower the Gleason score, the more the cancer cells look like normal cells and are likely to grow and spread slowly; a higher Gleason score is likely to indicate a worse outcome. The Gleason score is used to help plan treatment and determine prognosis.
• Percentage of Sample Considered Adenocarcinoma [Day 29 (prostatectomy)]: Tissues excised from the primary tumor during prostatectomy (Day 29) were evaluated for the percentage considered adenocarcinoma
• Concentration of Paclitaxel in the Systemic Circulation [Day 1, Day 8, Day 15, Day 22, and Day 29]: Pharmacokinetic samples were taken on Day 1 at 1, 2, 4, and 6 hours post-injection, and weekly until prostatectomy. All numeric paclitaxel concentration data above the Lower Limit of Quantitation (25 pg/mL) was tabulated by cohort.

Sex: Male, ages: 18 Years to any

Inclusion Criteria:

* Male; 18 years of age and older
* Histopathologically proven adenocarcinoma, Gleason grade ≥ 7 of the prostate planned radical prostatectomy; appropriate for treatment with paclitaxel therapy
* ECOG of 0 or 1
* Laboratory requirements:

  * WBC >2500/mm3
  * Neutrophil >1500/mm3
  * Hemoglobin >10 mg/dL
  * Platelet >100,000/ mm3
  * AST and ALT <2.5 x ULN
  * Total bilirubin <1.5 x ULN
  * Creatinine <2 mg/dL
  * Normal PT/INR and PTT;
* Willing to use appropriate contraception from time of NanoPac® injection until prostatectomy
* Willing to receive an mpMRI

Exclusion Criteria:

* Evidence of locally advanced or metastatic disease;
* Prostate size ≥ 50 cc
* Prior prostatectomy
* Anticipated use of concomitant chemotherapy (other than the protocol specified agents), immunotherapy, or systemic use of hormonal therapy (such as GnRH analogs, antiandrogens, androgen receptor inhibitors, and 5-α reductase inhibitors) prior to surgery
* Treatment with a prior investigational agent within 30 days of first dose of investigational medication
* Any previous local treatment of the prostate (i.e. radiation)
* Any other condition (e.g. psychiatric disorder) that, in the opinion of the Investigator, may interfere with the patient's ability to comply with the study requirements or visit schedule
* Known sensitivity to any of the study medication components
* History of prior malignancy that has not been in remission for >5 years, with the exception of basal cell or squamous cell carcinoma.

Participant flow

Outcome results

• Number of Participants With Treatment Emergent Adverse Events (Safety and Tolerability) (Primary), Count of participants, Participants: NanoPac® 6 mg/mL 3; NanoPac® 10 mg/mL 2; NanoPac® 15 mg/mL 6
• Tumor Response Based on Change in Image Volume on mpMRI (Secondary), Mean, cc: NanoPac® 6 mg/mL 3.19 +/- 1.46; NanoPac® 10 mg/mL 0.89 +/- 0.44; NanoPac® 15 mg/mL 4.89 +/- 5.12
• Tumor Response Based on Histologic Evaluation of Biopsied Prostate Samples (Gleason Score) (Secondary), Mean, score on a scale: NanoPac® 6 mg/mL 7.7 +/- 1.2; NanoPac® 10 mg/mL 7.0 +/- 0.0; NanoPac® 15 mg/mL 7.4 +/- 0.7
• Percentage of Sample Considered Adenocarcinoma (Secondary), Mean, percentage of sample adenocarcinoma: NanoPac® 6 mg/mL 53.3 +/- 5.8; NanoPac® 10 mg/mL 33.3 +/- 24.7; NanoPac® 15 mg/mL 47.5 +/- 22.0
• Concentration of Paclitaxel in the Systemic Circulation (Secondary), Mean, Plasma paclitaxel concentration (pg/mL): NanoPac® 6 mg/mL 5590.00 +/- 2312.336; NanoPac® 10 mg/mL 19673.33 +/- 20736.445; NanoPac® 15 mg/mL 19010.50 +/- 15105.857
• Change in PSA Density (Post hoc), Mean, ng/mL/cc: NanoPac® 6 mg/mL 3.64 +/- 5.75; NanoPac® 10 mg/mL 0.23 +/- 0.02; NanoPac® 15 mg/mL 0.31 +/- 0.31
• Change in PI-RADS Score (Post hoc), Count of participants, Participants: NanoPac® 6 mg/mL 1; NanoPac® 10 mg/mL 1; NanoPac® 15 mg/mL 1
• Tumor Invasion Into Surrounding Tissues (Post hoc), Count of participants, Participants: NanoPac® 6 mg/mL 2; NanoPac® 10 mg/mL 0; NanoPac® 15 mg/mL 4

Adverse events

Time frame: 28 days, from Day 1 (the day of NanoPac injection) to Day 29 (the day of prostatectomy)

Other adverse events by term

• Study Protocol (PDF, 2017-08-08)
• Statistical Analysis Plan (PDF, 2018-11-13)

• Shelagh Verco, PhD, Study director, US Biotest, Inc.