PEN-866 in Patients With Advanced Solid Malignancies

Tarveda Therapeutics

Status and phase: Unknown; Phase 2; Phase 1

Conditions: Solid Tumor; Small-cell Lung Cancer; Squamous Cell Carcinoma; Squamous Cell Carcinoma of the Vulva; Pancreatic Adenocarcinoma; Carcinoma; Adenocarcinoma of the Pancreas; Squamous Cell Carcinoma of the Anus; Pancreatic Ductal Adenocarcinoma; Small Cell Lung Carcinoma; Gastric Adenocarcinoma; Advanced Cancer; Endometrial Adenocarcinoma; Gastric Cancer; Squamous Cell Carcinoma of the Penis; Neoplasms; Solid Carcinoma; Gastroesophageal Junction Adenocarcinoma; Squamous Cell Carcinoma of the Cervix

Treatments: Drug: PEN-866 Sodium; Drug: fluorouracil; Drug: Folinic acid; Drug: Niraparib

Study type: Interventional

Funder types: Industry

Identifiers

NCT03221400

PEN-866-001

Details and patient eligibility

About

Protocol PEN-866-001 is an open-label, multi-center, first-in-human Phase 1/2a study evaluating PEN-866 in patients with advanced solid malignancies whose disease has progressed after treatment with previous anticancer therapies.

Full description

Phase 1a will employ an adaptive model guided with overdose control principle to make dose recommendations and estimate the maximum tolerated dose (MTD) of PEN-866 (single agent).

Phase 1b will employ a standard 3 + 3 design to make dose recommendations and estimate the MTD of PEN-866 in combination therapy.

Phase 2a (single agent) will assess the safety, tolerability, pharmacokinetic, and pharmacodynamics profile of PEN-866 (single agent) at the recommended Phase 2 dose determined at the conclusion of Phase 1a in patients with advanced solid malignancies.

Enrollment: 340 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

1. M/F at least 18 years old

2. Performance status 0 or 1

3. Adequate bone marrow, liver, and kidney function within 28 days prior to first dose

4. Serum potassium, calcium, magnesium, phosphorus within normal limits

5. Adequate birth control

6. Central venous access line is required

7. Patients in Phase 1a must also have confirmed advanced solid malignancy that has progressed after one or more prior lines of anticancer therapy and no other standard of care therapies that are deemed appropriate for treatment of their malignancy

8. Patients in Phase 2a must have measurable disease per RECIST 1.1 and documented disease progression during or after their most recent line of anticancer therapy.

9. Patients in Phase 2a must have disease history specific to their disease as listed below:

   • Small Cell Lung Cancer (SCLC): Patients with locally recurrent or metastatic SCLC whose disease has progressed after having received one or more prior lines of chemotherapy.
   • Gastric or gastroesophageal (GEJ) adenocarcinoma: Patients with locally recurrent or metastatic gastric or GEJ adenocarcinoma whose disease has progressed after having received one or more prior lines of chemotherapy.
   • Squamous cell carcinoma (SCC) of the genitalia (anus, cervix, vulva, or penis): Patients with locally recurrent or metastatic SCC of the genitalia (anus, cervix, vulva, or penis) whose disease has progressed after having received one or more prior lines of chemotherapy, including those whose disease has progressed after postoperative adjuvant chemotherapy or neoadjuvant chemotherapy prior to radiation or surgery.
   • Pancreatic adenocarcinoma (PDAC): Patients with locally recurrent or metastatic PDAC whose disease has progressed after having received one or more prior lines of chemotherapy, including those whose disease has progressed within 6 months of postoperative adjuvant chemotherapy.
   • Endometrial adenocarcinoma (EC): Patients with locally recurrent or metastatic EC whose disease has progressed after having received one or more prior lines of chemotherapy, including those whose disease has progressed within 6 months of postoperative adjuvant chemotherapy.

10. For Phase 1b patients receiving PEN-866 in combination with fluorouracil and folinic acid only:

    • Patients with metastatic PDAC who have progressed after having received one or more prior lines of chemotherapy, including those whose disease has progressed within 6 months of postoperative adjuvant chemotherapy.

11. For Phase 1b patients receiving the Niraparib combination only:

    • Patients must have confirmed advanced solid malignancy that has progressed after one or more prior lines of anticancer therapy and no other standard of care therapies that are deemed appropriate for treatment of their malignancy

Exclusion criteria

1. Treatment with anticancer therapy or investigational drug or device within 2 wk (6 wk for nitrosureas or mitomycin C) before C1D1, and any drug-related toxicities must have recovered to grade 1 or less with the exception of alopecia and peripheral neuropathy.

2. Phase 2a only: Prior treatment with topoisomerase I inhibitor(s).

3. Cardiac disease such as unstable angina within 6 months of screening, myocardial infarction within 6 months of screening, NY Heart Association Class III - IV heart failure, QTc greater than 470 msec, congenital long Qt syndrome, symptomatic orthostatic hypotension within 6 months of screening, uncontrolled hypertension, or clinically important abnormalities in heart rhythm, conduction, morphology of resting ECG.

   -For Phase 1b patients receiving the Niraparib combination only: hypertension as defined as diastolic > 90 mmHg or systolic > 140 mmHg

4. Stroke or transient ischemic attack within 6 months of screening

5. Prior history of posterior reversible excephalopathy scyndrome (PRES).

6. Peripheral neuropathy greater than grade 2

7. Patients requiring medications with drugs that are inhibitors of UGT1A1 or substrates of CYP1A2, P-gP, BCRP, OATP1B1, OATP1B3 or OCT1 transporters

8. Leptomeningeal disease or spinal cord compression unless controlled and asymptomatic with surgery, radiation, and not requiring steroids within 4 weeks prior to C1D1.

9. Brain metastases unless previously treated and asymptomatic. Stable low dose of steroids is permitted.

10. Major surgery within 28 days of first drug dose

11. If female, pregnant or breast feeding

12. Evidence of severe uncontrolled systemic disease, bleeding diatheses, renal or liver transplant, active infection with hep B or C or HIV

13. Hypersensitivity or anaphylactic reaction to ganetespib or other HSP90 inhibitors, irinotecan, SN-38 or its derivatives

14. Any medical, psychological, or social condition that would interfere with the patient's participation in the study.

15. Live virus and bacterial vaccines administered within 30 days prior to C1D1.

16. Any medical, psychological, or social condition that would interfere with the patient's participation in the study.

    For Phase 1b patients receiving niraparib combination only, the following additional exclusion criteria apply:

17. Prior treatment with niraparib.

18. Current active liver or biliary disease (with the exception of Gilbert's syndrome or asymptomatic gallstones, liver metastatses or otherwise stable chronic liver disease per investigator assessment).

19. Severe hepatic impairment.

20. Treatment with transfusions and/or erythropoietin for the treatment of anemia within 4 weeks prior to C1D1.

21. Any known or current diagnosis of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML).

22. History of prostate cancer.

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Single Group Assignment

Masking: None (Open label)

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340 participants in 4 patient groups

Phase 1a PEN-866 Sodium (Single Agent)

Experimental group

Description:

Dose escalation of PEN-866 Sodium administered intravenously

Treatment:

Drug: PEN-866 Sodium

Phase 1b PEN-866 Sodium + Flurouracil + Folinic Acid

Experimental group

Description:

Dose escalation of intravenous administration of PEN-866 Sodium in combination with fluorouracil and folinic acid

Treatment:

Drug: PEN-866 Sodium

Drug: Folinic acid

Drug: fluorouracil

Phase 2a PEN-866 Sodium (Single Agent)

Experimental group

Description:

Intravenously administered PEN-866 Sodium at the Recommended Phase 2 Dose

Treatment:

Drug: PEN-866 Sodium

Phase 1b PEN-866 Sodium + Niraparib

Experimental group

Description:

Dose escalation of intravenous administration of PEN-866 Sodium in combination with niraparib

Treatment:

Drug: PEN-866 Sodium

Drug: Niraparib