Clinical trial NCT03221400: PEN-866 in Patients With Advanced Solid Malignancies
Official title: A Phase 1/2a, Open-label, Multicenter Study to Assess the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Preliminary Anti-tumor Activity of PEN-866 in Patients With Advanced Solid Malignancies
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE1
PHASE2
Conditions: Carcinoma
Endometrial Adenocarcinoma
Neoplasms
Squamous Cell Carcinoma of the Anus
Adenocarcinoma of the Pancreas
Advanced Cancer
Solid Tumor
Solid Carcinoma
Squamous Cell Carcinoma of the Cervix
Squamous Cell Carcinoma
Squamous Cell Carcinoma of the Vulva
Squamous Cell Carcinoma of the Penis
Gastric Cancer
Gastric Adenocarcinoma
Gastroesophageal Junction Adenocarcinoma
Small-cell Lung Cancer
Small Cell Lung Carcinoma
Pancreatic Ductal Adenocarcinoma
Pancreatic Adenocarcinoma
Lead sponsor: Tarveda Therapeutics
Sponsor class: INDUSTRY
First posted: 2017-07-18
Enrollment: 340
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.

Detailed 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Phase 1a and 1b : Incidence of Dose-Limiting Toxicities (DLTs)
timeFrame: Patients will be followed for 28 days to determine the incidence of DLTs.
measure: All Phases: Incidence of treatment related adverse events (Safety and tolerability)
timeFrame: From date of first treatment/trial entry up to 28 days following the last treatment.
measure: Phase 2a: Efficacy of PEN-866 in patients with SCLC using best overall response rate
timeFrame: From the date of first treatment through the date of first documented progression, assessed up to (estimated) 18 months
measure: Phase 2a: Efficacy of PEN-866 in patients with gastric or gastroesophageal junction (GEJ) adenocarcinoma using best overall response rate
timeFrame: From the date of first treatment through the date of first documented progression, assessed up to (estimated) 18 months
measure: Phase 2a: Efficacy of PEN-866 in patients with pancreatic adenocarcinoma using Disease Control Rate (DCR)
timeFrame: From the date of first treatment through the date of first documented progression, assessed up to (estimated) 18 months
measure: Phase 2a: Efficacy of PEN-866 in patients with endometrial adenocarcinoma using best overall response rate
timeFrame: From the date of first treatment through the date of first documented progression, assessed up to (estimated) 18 months
measure: Phase 2a: Efficacy of PEN-866 in patients with squamous cell carcinoma of the genitalia (anus, cervix, vulva, or penis) using best overall response rate
timeFrame: From the date of first treatment through the date of first documented progression, assessed up to (estimated) 18 months
Secondary outcomes:
measure: Maximum concentration (Cmax) of PEN-866 and its components (HSP90 ligand and SN-38)
timeFrame: 1 Month (Phase 1a); 14 days (Phase 1b); assessed up to (estimated) 18 months for Phase 2a
measure: Area under the curve (AUC) of PEN-866 and its components (HSP90 ligand and SN-38)
timeFrame: 1 Month (Phase 1a); 14 days (Phase 1b); assessed up to (estimated) 18 months for Phase 2a
measure: Half-life (t1/2) of PEN-866 and its components (HSP90 ligand and SN-38)
timeFrame: 1 Month (Phase 1a); 14 days (Phase 1b); assessed up to (estimated) 18 months for Phase 2a
measure: Phase 1b: Characterize the plasma pharmacokinetics (PK) of the combination therapies and their components
timeFrame: 14 days
measure: Phase 1a: Tumor response using RECIST 1.1 criteria
timeFrame: Baseline and every 6 weeks until date of first documented progression or death (estimated 6 months)
measure: Phase 1b: Disease Control Rate
timeFrame: From date of first treatment through the date of date of first documented progression, assessed up to (estimated) 18 months
measure: Phase 2a: Disease Control Rate in patients with SCLC, gastric or gastroesophageal junction adenocarcinoma, endometrial adenocarcinoma, and squamous cell carcinoma of the genitalia (anus, cervix, vulva, and penis)
timeFrame: From date of first treatment through the date of date of first documented progression, assessed up to (estimated) 18 months
measure: Phase 2a: Evaluate the best overall response rate in patients with pancreatic adenocarcinoma
timeFrame: From date of first treatment through the date of first documented progression, assessed up to (estimated) 18 months
measure: Phase 1b and 2a: Duration of Response
timeFrame: From date of first treatment until the date of date of death from any cause, assessed up to (estimated) 18 months
measure: Phase 2a: Radiographic progression free survival
timeFrame: From date of first treatment until the date of first documented progression or date of death from any cause, whichever is first, assessed up to (estimated) 18 months
measure: Phase 2a: Overall survival
timeFrame: From date of first treatment until the date of date of death from any cause, assessed up to (estimated) 18 months
Other outcomes:
Locations:
city: Springdale
country: United States
facility: Highlands Oncology Group
state: Arkansas
city: Denver
country: United States
facility: Sarah Cannon Reasearch Institute at HealthONE
state: Colorado
city: Fort Myers
country: United States
facility: Florida Cancer Specialists - South
state: Florida
city: Saint Petersburg
country: United States
facility: Florida Cancer Specialists - North
state: Florida
city: West Palm Beach
country: United States
facility: Florida Cancer Specialists - East
state: Florida
city: Bethesda
country: United States
facility: National Institutes of Health / National Cancer Institute
state: Maryland
city: Detroit
country: United States
facility: Henry Ford
state: Michigan
city: Omaha
country: United States
facility: Nebraska Cancer Specialists
state: Nebraska
city: Las Vegas
country: United States
facility: Comprehensive Cancer Centers of Nevada
state: Nevada
city: Oklahoma City
country: United States
facility: Stephenson Cancer Center, University of Oklahoma
state: Oklahoma
city: Philadelphia
country: United States
facility: Sidney Kimmel Cancer Center at Thomas Jefferson University Hospital
state: Pennsylvania
city: Greenville
country: United States
facility: Prisma Health - Upstate
state: South Carolina
city: Germantown
country: United States
facility: The West Clinic
state: Tennessee
city: Nashville
country: United States
facility: Tennessee Oncology
state: Tennessee
city: Fairfax
country: United States
facility: Virginia Cancer Specialists
state: Virginia
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
Study officials:
affiliation: National Cancer Institute (NCI)
name: Anish Thomas, MD
role: STUDY_CHAIR
References: