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PEN-866 in Patients With Advanced Solid Malignancies

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ClinicalTrials.gov Identifier: NCT03221400
Recruitment Status : Recruiting
First Posted : July 18, 2017
Last Update Posted : November 13, 2020
Sponsor:
Information provided by (Responsible Party):
Tarveda Therapeutics

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.

Condition or disease Intervention/treatment Phase
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 Drug: PEN-866 Sodium Drug: fluorouracil Drug: Folinic acid Phase 1 Phase 2

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 combination therapy in patients with pancreatic adenocarcinoma (PDAC).

Phase 2a (single agent) begins once all patients treated in Phase 1a have been assessed for safety and the Safety Review Committee (SRC) has reviewed all safety data and recommends continuing with Phase 2a. PEN-866 will be evaluated using the recommended Phase 2 dose identified by the SRC at the conclusion of Phase 1a (single agent) based on the safety, tolerability, pharmacokinetic, and pharmacodynamics profile of PEN-866 (single agent)during Phase 1a.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 290 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : August 29, 2017
Estimated Primary Completion Date : December 2021
Estimated Study Completion Date : June 2022


Arm Intervention/treatment
Experimental: Phase 1a PEN-866 Sodium (Single Agent)
Dose escalation of PEN-866 Sodium administered intravenously
Drug: PEN-866 Sodium
PEN-866 Sodium is a miniaturized conjugate that comprises an HSP90 targeting ligand linked to SN-38, the active metabolite of irinotecan. PEN-866 is available as a sterile lyophilized powder for solution for infusion.

Experimental: Phase 1b PEN-866 Sodium + Flurouracil + Folinic Acid
Dose escalation of intravenous administration of PEN-866 Sodium in combination with fluorouracil and folinic acid
Drug: PEN-866 Sodium
PEN-866 Sodium is a miniaturized conjugate that comprises an HSP90 targeting ligand linked to SN-38, the active metabolite of irinotecan. PEN-866 is available as a sterile lyophilized powder for solution for infusion.

Drug: fluorouracil
Fluorouracil 2400 mg/m2 IV
Other Names:
  • 5-Fluorouracil
  • 5-FU

Drug: Folinic acid
Folinic acid 400 mg/m2 IV
Other Name: Leucovorin

Experimental: Phase 2a PEN-866 Sodium (Single Agent)
Intravenously administered PEN-866 Sodium at the Recommended Phase 2 Dose
Drug: PEN-866 Sodium
PEN-866 Sodium is a miniaturized conjugate that comprises an HSP90 targeting ligand linked to SN-38, the active metabolite of irinotecan. PEN-866 is available as a sterile lyophilized powder for solution for infusion.




Primary Outcome Measures :
  1. 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. ]
    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).

  2. All Phases: Incidence of treatment related adverse events (Safety and tolerability) [ Time Frame: From date of first treatment/trial entry up to 28 days following the last treatment. ]
    Safety and tolerability will be determined by assessing the incidence of treatment related adverse events.

  3. Phase 2a: Efficacy of PEN-866 in patients with SCLC using best overall response rate [ Time Frame: From the date of first treatment through the date of first documented progression, assessed up to (estimated) 18 months ]
    Efficacy of PEN-866 in patients with SCLC will be assessed using best overall tumor response rate defined as complete response (CR) or partial response (PR) according to RECIST 1.1.

  4. Phase 2a: Efficacy of PEN-866 in patients with gastric or gastroesophageal junction (GEJ) adenocarcinoma using best overall response rate [ Time Frame: From the date of first treatment through the date of first documented progression, assessed up to (estimated) 18 months ]
    Efficacy of PEN-866 in patients with gastric or GEJ adenocarcinoma will be assessed using best overall tumor response rate defined as CR or PR according to RECIST 1.1.

  5. Phase 2a: Efficacy of PEN-866 in patients with pancreatic adenocarcinoma using Disease Control Rate (DCR) [ Time Frame: From the date of first treatment through the date of first documented progression, assessed up to (estimated) 18 months ]
    Efficacy of PEN-866 in patients with pancreatic adenocarcinoma will be assessed using DCR defined as a best response of CR, PR, or stable disease (SD) according to RECIST 1.1.

  6. Phase 2a: Efficacy of PEN-866 in patients with endometrial adenocarcinoma using best overall response rate [ Time Frame: From the date of first treatment through the date of first documented progression, assessed up to (estimated) 18 months ]
    Efficacy of PEN-866 in patients with endometrial adenocarcinoma will be assessed using best over all tumor response rate defined as CR or PR according to RECIST 1.1.

  7. 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 [ Time Frame: From the date of first treatment through the date of first documented progression, assessed up to (estimated) 18 months ]
    Efficacy of PEN-866 in patients with squamous cell carcinoma of the genitalia will be assessed using best over all tumor response rate defined as CR or PR according to RECIST 1.1.


Secondary Outcome Measures :
  1. 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 ]
    Characterize the pharmacokinetic properties of PEN-866 and its components (HSP90 targeting ligand and SN-38)

  2. 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 ]
    Characterize the pharmacokinetic properties of PEN-866 and its components (HSP90 targeting ligand and SN-38)

  3. 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 ]
    Characterize the pharmacokinetic properties of PEN-866 and its components (HSP90 targeting ligand and SN-38)

  4. Phase 1b: Characterize the plasma pharmacokinetics (PK) of the combination therapies and their components [ Time Frame: 14 days ]
    PK parameters (CMax, AUC) will be evaluated in plasma by standard non-compartmental methods (compartmental modeling may be performed if appropriate).

  5. 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) ]
    Size of tumors by CT or MRI using tumor response criteria according to RECIST 1.1 and duration of response.

  6. 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 ]
    Efficacy of PEN-866 in combination therapy will be assessed using DCR as defined as CR, PR, or SD according to RECIST 1.1.

  7. 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 ]
    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.

  8. 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 ]
    Efficacy of PEN-866 in pancreatic adenocarcinoma using best overall tumor response rate as defined as CR or PR according to RECIST 1.1

  9. 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 ]
    Time from first documented response (CR or PR) to date of first documented disease progression or death due to underlying cancer.

  10. 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 ]
    Time from first PEN-866 dose to date of first documented progression or date of death from any cause, whichever came first

  11. 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 ]
    Time from first PEN-866 dose to date of death from any cause



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 and Phase 1b 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 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.

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
  4. Stroke or transient ischemic attack within 6 months of screening
  5. Peripheral neuropathy greater than grade 2
  6. Patients requiring medications with drugs that are inhibitors of UGT1A1 or substrates of CYP1A2, P-gP, BCRP, OATP1B1, OATP1B3 or OCT1 transporters
  7. History of leptomeningeal disease or spinal cord compression
  8. Brain metastases unless asymptomatic. Stable low dose of steroids is permitted.
  9. As judge by the Investigator major surgery within 28 days of first drug dose
  10. Female pregnant or breast feeding
  11. Evidence of severe uncontrolled systemic disease, bleeding diatheses, renal or liver transplant, active infection with hep B or C or HIV
  12. Hypersensitivity or anaphylactic reaction to ganetespib or other HSP90 inhibitors, irinotecan, SN-38 or its derivatives
  13. Any medical, psychological, or social condition that would interfere with the patient's participation in the study.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03221400


Contacts
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Contact: Tarveda Clinical Information Center (617) 923-4100 clinical.information@tarvedatx.com

Locations
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United States, Colorado
Sarah Cannon Reasearch Institute at HealthONE Recruiting
Denver, Colorado, United States, 80218
United States, Florida
Florida Cancer Specialists - South Recruiting
Fort Myers, Florida, United States, 33901
Florida Cancer Specialists - North Recruiting
Saint Petersburg, Florida, United States, 33705
Florida Cancer Specialists - East Recruiting
West Palm Beach, Florida, United States, 33401
United States, Maryland
National Institutes of Health / National Cancer Institute Recruiting
Bethesda, Maryland, United States, 20892
United States, Nevada
Comprehensive Cancer Centers of Nevada Recruiting
Las Vegas, Nevada, United States, 89169
United States, Oklahoma
Stephenson Cancer Center, University of Oklahoma Recruiting
Oklahoma City, Oklahoma, United States, 73104
United States, South Carolina
Prisma Health - Upstate Recruiting
Greenville, South Carolina, United States, 29605
United States, Tennessee
The West Clinic Recruiting
Germantown, Tennessee, United States, 38138
Tennessee Oncology Recruiting
Nashville, Tennessee, United States, 37203
Sponsors and Collaborators
Tarveda Therapeutics
Investigators
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Study Chair: Anish Thomas, MD National Cancer Institute (NCI)
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Responsible Party: Tarveda Therapeutics
ClinicalTrials.gov Identifier: NCT03221400    
Other Study ID Numbers: PEN-866-001
First Posted: July 18, 2017    Key Record Dates
Last Update Posted: November 13, 2020
Last Verified: November 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Carcinoma
Carcinoma, Squamous Cell
Adenocarcinoma
Small Cell Lung Carcinoma
Anus Neoplasms
Vulvar Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Squamous Cell
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Gastrointestinal Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms
Lung Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Lung Diseases
Respiratory Tract Diseases
Rectal Neoplasms
Colorectal Neoplasms
Intestinal Neoplasms
Intestinal Diseases
Anus Diseases
Rectal Diseases
Genital Neoplasms, Female
Urogenital Neoplasms