Clinical Trials /

PEN-866 in Patients With Advanced Solid Malignancies

NCT03221400

Description:

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.

Related Conditions:
  • Adenocarcinoma of the Gastroesophageal Junction
  • Anal Squamous Cell Carcinoma
  • Cervical Squamous Cell Carcinoma
  • Endometrial Adenocarcinoma
  • Gastric Adenocarcinoma
  • Malignant Solid Tumor
  • Pancreatic Adenocarcinoma
  • Small Cell Lung Carcinoma
  • Squamous Cell Carcinoma of the Penis
  • Vulvar Squamous Cell Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: 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

Clinical Trial IDs

  • ORG STUDY ID: PEN-866-001
  • NCT ID: NCT03221400

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

Interventions

DrugSynonymsArms
PEN-866 SodiumPhase 1a PEN-866 Sodium (Single Agent)
fluorouracil5-Fluorouracil, 5-FUPhase 1b PEN-866 Sodium + Flurouracil + Folinic Acid
Folinic acidLeucovorinPhase 1b PEN-866 Sodium + Flurouracil + Folinic Acid
NiraparibZejulaPhase 1b PEN-866 Sodium + Niraparib

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
Phase 1a PEN-866 Sodium (Single Agent)ExperimentalDose escalation of PEN-866 Sodium administered intravenously
  • PEN-866 Sodium
Phase 1b PEN-866 Sodium + Flurouracil + Folinic AcidExperimentalDose escalation of intravenous administration of PEN-866 Sodium in combination with fluorouracil and folinic acid
  • PEN-866 Sodium
  • fluorouracil
  • Folinic acid
Phase 2a PEN-866 Sodium (Single Agent)ExperimentalIntravenously administered PEN-866 Sodium at the Recommended Phase 2 Dose
  • PEN-866 Sodium
Phase 1b PEN-866 Sodium + NiraparibExperimentalDose escalation of intravenous administration of PEN-866 Sodium in combination with niraparib
  • PEN-866 Sodium
  • Niraparib

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.

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

         16. Prior treatment with niraparib.

         17. 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).

         18. Severe hepatic impairment.

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

         20. Any known or current diagnosis of myelodysplastic syndrome (MDS) or acute myeloid
             leukemia (AML).
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Phase 1a and 1b : Incidence of Dose-Limiting Toxicities (DLTs)
Time Frame:Patients will be followed for 28 days to determine the incidence of DLTs.
Safety Issue:
Description:The Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) will be determined by assessing the incidence of DLTs and treatment related adverse events of PEN-866 as a single agent (Phase 1a) or in combination therapy (Phase 1b).

Secondary Outcome Measures

Measure:Maximum concentration (Cmax) of PEN-866 and its components (HSP90 ligand and SN-38)
Time Frame:1 Month (Phase 1a); 14 days (Phase 1b); assessed up to (estimated) 18 months for Phase 2a
Safety Issue:
Description:Characterize the pharmacokinetic properties of PEN-866 and its components (HSP90 targeting ligand and SN-38)
Measure:Area under the curve (AUC) of PEN-866 and its components (HSP90 ligand and SN-38)
Time Frame:1 Month (Phase 1a); 14 days (Phase 1b); assessed up to (estimated) 18 months for Phase 2a
Safety Issue:
Description:Characterize the pharmacokinetic properties of PEN-866 and its components (HSP90 targeting ligand and SN-38)
Measure:Half-life (t1/2) of PEN-866 and its components (HSP90 ligand and SN-38)
Time Frame:1 Month (Phase 1a); 14 days (Phase 1b); assessed up to (estimated) 18 months for Phase 2a
Safety Issue:
Description:Characterize the pharmacokinetic properties of PEN-866 and its components (HSP90 targeting ligand and SN-38)
Measure:Phase 1b: Characterize the plasma pharmacokinetics (PK) of the combination therapies and their components
Time Frame:14 days
Safety Issue:
Description:PK parameters (CMax, AUC) will be evaluated in plasma by standard non-compartmental methods (compartmental modeling may be performed if appropriate).
Measure:Phase 1a: Tumor response using RECIST 1.1 criteria
Time Frame:Baseline and every 6 weeks until date of first documented progression or death (estimated 6 months)
Safety Issue:
Description:Size of tumors by CT or MRI using tumor response criteria according to RECIST 1.1 and duration of response.
Measure:Phase 1b: Disease Control Rate
Time Frame:From date of first treatment through the date of date of first documented progression, assessed up to (estimated) 18 months
Safety Issue:
Description:Efficacy of PEN-866 in combination therapy will be assessed using DCR as defined as CR, PR, or SD according to RECIST 1.1.
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)
Time Frame:From date of first treatment through the date of date of first documented progression, assessed up to (estimated) 18 months
Safety Issue:
Description:Efficacy of PEN-866 in SCLC, gastric or gastroesophageal junction adenocarcinoma, endometrial adenocarcinoma, and squamous cell carcinoma of the genitalia (anus, cervix, vulva, and penis) will be assessed using DCR as defined as CR, PR, or SD according to RECIST 1.1.
Measure:Phase 2a: Evaluate the best overall response rate in patients with pancreatic adenocarcinoma
Time Frame:From date of first treatment through the date of first documented progression, assessed up to (estimated) 18 months
Safety Issue:
Description:Efficacy of PEN-866 in pancreatic adenocarcinoma using best overall tumor response rate as defined as CR or PR according to RECIST 1.1
Measure:Phase 1b and 2a: Duration of Response
Time Frame:From date of first treatment until the date of date of death from any cause, assessed up to (estimated) 18 months
Safety Issue:
Description:Time from first documented response (CR or PR) to date of first documented disease progression or death due to underlying cancer.
Measure:Phase 2a: Radiographic progression free survival
Time Frame: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
Safety Issue:
Description:Time from first PEN-866 dose to date of first documented progression or date of death from any cause, whichever came first
Measure:Phase 2a: Overall survival
Time Frame:From date of first treatment until the date of date of death from any cause, assessed up to (estimated) 18 months
Safety Issue:
Description:Time from first PEN-866 dose to date of death from any cause

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Tarveda Therapeutics

Last Updated

March 10, 2021