A Study of HC-5404-FU to Establish the Maximum Tolerated Dose (MTD)

NCT04834778 | Completed Phase 1 FDA Drug

• 1 other identifier: HC-404-FCP-2011
• Study Type: interventional
• Target: 23
• Locations: 1 country
• Sites: 4

Brief Summary

Study HC-404-FCP-2011 is a first in human, Phase 1a, multi-center, open-label study to establish the maximum tolerated dose (MTD) and evaluate the safety and tolerability of oral dosing of HC-5404-FU in a dose-escalating fashion. Up to 36 qualified subjects at 3 to 5 US sites, who have specific tumor types of renal cell carcinoma (RCC), gastric cancer (GC), metastatic breast cancer (MBC), small cell lung cancer (SCLC), and other solid tumors (e.g., non-small cell lung cancer, colorectal cancer, carcinoma of unknown primary) with the exception of rapidly progressing neoplasms (e.g., pancreatic cancer, glioblastoma, hepatocellular carcinoma) will receive HC-5404-FU. Every effort will be made to ensure approximately 50% of all subjects enrolled will be subjects with RCC and GC. The starting dose level is 25 mg twice daily (BID), escalating to 50, 100, and 200 mg BID as safety allows, following the Bayesian Optimal Interval (BOIN) design. The safety monitoring committee (SMC) will evaluate the DLTs and cumulative safety and PK data at the end of each cohort. Based on the SMC recommendations after a comprehensive review of PK and safety data for 200 mg BID dose, higher dose levels will be evaluated, starting with 400 mg BID. The dose will escalate to 600 mg and then 900 mg following the BOIN design starting with 1 subject at each escalated dose, until the MTD is reached or the sponsor or SMC declares the dose most appropriate for clinical development. This Phase 1a will be expanded into a Phase 1b/2a study through a protocol amendment and will then assess the dose and tumor type(s) selected in Phase 1a as the most appropriate for further clinical development. Subjects will be dosed until unacceptable toxicity, disease progression per immune-related Response Evaluation Criteria in Solid Tumors (iRECIST), subject withdrawal, any other administrative reasons, or after 2 years of treatment, whichever occurs first. Efficacy will be assessed via Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1); computed tomography (CT) scans will be conducted every 6 weeks. Safety, including occurrence of dose-limiting toxicities (DLTs), pharmacokinetics (PK), and biomarker parameters will also be assessed.

Conditions

Renal Cell Carcinoma; Gastric Cancer; Metastatic Breast Cancer; Small-cell Lung Cancer; Other Solid Tumors

Keywords

RCC; GC; MCA; SCLC; Phase 1; First in human; HC-5404-FU; HC-5404

Outcome Measures

Primary Outcomes (7)

• Determination of MTD of HC-5404-FU

  When orally administered in a dose escalating fashion in subjects with selected, advanced solid tumors

  Within 18 months of last patient enrolled

• Occurrence of dose-limiting toxicities (DLTs)

  Within 18 months of last patient enrolled

• Incidence and severity of treatment-emergent adverse events (TEAEs) and treatment related TEAEs according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v 5.0

  Within 18 months of last patient enrolled

• Incidence of TEAEs leading to premature discontinuation

  Within 18 months of last patient enrolled

• Incidence of significant laboratory abnormalities, based on hematology, serum chemistry, and urinalysis test results

  Within 18 months of last patient enrolled

• Incidence of abnormalities observed in 12 lead ECG parameters

  Within 18 months of last patient enrolled

• Incidence of abnormalities observed in vital signs measurements and physical examinations

  Within 18 months of last patient enrolled

Secondary Outcomes (16)

• Area under the plasma concentration versus time curve from time 0 until last measurable concentration (AUC0 last)

  Within 24 months of last patient enrolled

• Area under the plasma concentration versus time curve from time 0 to 12 hours postdose (AUC0 12)

  Within 24 months of last patient enrolled

• Area under the plasma concentration versus time curve from time 0 extrapolated to infinity (AUC0 ∞)

  Within 24 months of last patient enrolled

• Area under the plasma concentration versus time curve over a dosing interval (AUC0 t)

  Within 24 months of last patient enrolled

• Peak plasma concentration (Cmax)

  Within 24 months of last patient enrolled

Study Arms (8)

Cohort 1 - 25 mg

EXPERIMENTAL

25 mg capsules of HC-5404-FU administered orally twice a day with food or within 30 minutes of completing a meal of each 3-week treatment cycle

Drug: HC-5404-FU

Cohort 2 - 50 mg

EXPERIMENTAL

50 mg capsules of HC-5404-FU administered orally twice a day with food or within 30 minutes of completing a meal of each 3-week treatment cycle

Drug: HC-5404-FU

Cohort 3 - 100 mg

EXPERIMENTAL

100 mg capsules of HC-5404-FU administered orally twice a day with food or within 30 minutes of completing a meal of each 3-week treatment cycle

Drug: HC-5404-FU

Cohort 4 - 200 mg

EXPERIMENTAL

200 mg capsules of HC-5404-FU administered orally twice a day with food or within 30 minutes of completing a meal of each 3-week treatment cycle

Drug: HC-5404-FU

Cohort 5 - 400 mg

EXPERIMENTAL

400 mg capsules of HC-5404-FU administered orally twice a day with food or within 30 minutes of completing a meal of each 3-week treatment cycle

Drug: HC-5404-FU

Cohort 6 - 600 mg

EXPERIMENTAL

600 mg capsules of HC-5404-FU administered orally twice a day with food or within 30 minutes of completing a meal of each 3-week treatment cycle

Drug: HC-5404-FU

Cohort 7 - 900 mg

EXPERIMENTAL

900 mg capsules of HC-5404-FU administered orally twice a day with food or within 30 minutes of completing a meal of each 3-week treatment cycle

Drug: HC-5404-FU

Cohort 8 - 300 mg

EXPERIMENTAL

300 mg capsules of HC-5404-FU administered orally twice a day with food or within 30 minutes of completing a meal of each 3-week treatment cycle

Drug: HC-5404-FU

Interventions

HC-5404-FU DRUG

HC 5404-FU (hemi fumarate salt of HC 5404) is a novel, highly selective, and potent PERK inhibitor. Preclinical pharmacological studies demonstrated high specificity of HC 5404-FU to PERK and decreased viability of tumor cells. HC 5404-FU will be orally administered BID every day with food or within 30 minutes of completing a meal, starting at 25 mg, with doses escalating to 50, 100, 200, 400, 600, and 900 mg BID as safety allows for each 3-week treatment cycle.

Also known as: HC-5404

Cohort 1 - 25 mg; Cohort 2 - 50 mg; Cohort 3 - 100 mg; Cohort 4 - 200 mg; Cohort 5 - 400 mg; Cohort 6 - 600 mg; Cohort 7 - 900 mg; Cohort 8 - 300 mg

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Have a signed informed consent form prior to any study specific procedures or treatment
• Be ≥18 years of age (male or female) at the time of consent
• Have 1 of the following histologically or cytologically confirmed tumor types with qualifying characteristics, and have received a minimum of 2 (and no more than 5) lines of prior therapy for metastatic (Stage IV) disease:
• RCC (renal cell carcinoma - clear cell or papillary)
• SCLC (small cell lung cancer) OR have received a minimum of 3 (and no more than 5) lines of prior therapy for metastatic (Stage IV) disease:
• GC (gastric adenocarcinoma)
• Human epidermal growth factor receptor positive (HER2+) MBC (metastatic breast cancer)
• Other solid tumors (e.g., non-small cell lung cancer, colorectal cancer, carcinoma of unknown primary) with the exception of rapidly progressing neoplasms (e.g., pancreatic cancer, glioblastoma, hepatocellular carcinoma)
• Note: Subjects with RCC and GC are a priority and should constitute approximately 50% (12 subjects) of the enrolled popululation. Enrollment of all others will be capped when reaching a combined 50%, in order to maintain 12 slots for subjects with RCC and GC.
• Have at least 1 radiologically measurable lesion as per RECIST v 1.1, defined as a lesion that is at least 10 mm in longest diameter or lymph node and that is at least 15 mm in short axis imaged by CT scan or magnetic resonance imaging (MRI) and obtained by imaging within 28 days prior to screening. Tumor lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions
• Have resolution of all previous treatment related toxicities to Grade 1 severity or lower, except for stable sensory neuropathy (≤ Grade 2) and alopecia. If the subject received major surgery or radiation therapy of \>30 Gy, they must have recovered from the toxicity and/or complications from the intervention
• Provided there are suitable and accessible lesions, no biopsy contraindications, minimal risk of complications and a positive informed decision, subject as are willing to provide fresh tissue for biomarker analysis, and, based on the adequacy of the tissue sample quality, for assessment of biomarker status. Two biopsies will be necessary: at baseline (within 30 days prior to first dose) and within 7 days after Cycle 3/Day 1.
• Newly obtained biopsy specimens are preferred to archived samples and formalin- fixed, paraffin-embedded block specimens are preferred to slides. In the event a fresh pre-treatment biopsy is not able to be provided, the most recent archival biopsy must be provided in its place
• Have Eastern Cooperative Oncology Group performance status of 0 or 1 and sustained between screening and initiation of dosing on Day 1
• QT interval corrected for heart rate using Fridericia's (QTcF) method ≤450 msec

You may not qualify if:

• Had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to the first dose of study treatment or who has not recovered from adverse reactions due to a previously administered agent or major surgery
• Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment
• Has a diagnosis of immunodeficiency or receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment. The use of physiologic doses of corticosteroids (≤30 mg/day of hydrocortisone, ≤10 mg/day of prednisone, ≤2 mg/day of dexamethasone, or equivalent) may be approved after consultation with the sponsor
• Has taken a medication that is a strong CYP3A4 inhibitor or inducer within 4 weeks of the first dose of treatment (see Appendix 12)
• Has known history of active tuberculosis
• Has known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)
• Has known active Hepatitis B (anti hepatitis B surface antibody, anti hepatitis B core antibody, hepatitis B surface antigen \[HBsAg\]) or Hepatitis C (hepatitis C antibody) infection
• Has a current diagnosis of severe acute respiratory syndrome coronavirus (SARS CoV) 2 infection confirmed by reverse transcription polymerase chain reaction (PCR) test. Subject needs to have a negative PCR test at screening and a negative PCR test within 14 days prior to the first dose of study treatment
• Has a history of clinically severe autoimmune disease, or a history of organ transplant
• Has insulin dependent (Type I) diabetes or poorly controlled Type II diabetes (per clinical discretion) with hemoglobin A1c \>8%
• Has known additional malignancy that is progressing or required active treatment within previous 5 years. Exceptions include basal cell carcinoma or squamous cell carcinoma of the skin that has undergone potentially curative therapy, superficial bladder cancer, or in situ cervical cancer. Subjects with other malignancies are eligible if they were cured by surgery alone or surgery plus radiotherapy and have been continuously disease free for at least 5 years
• Has known active central nervous system metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of disease progression by imaging for at least 4 weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using systemic steroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability
• Has a history of interstitial lung disease, pneumonitis within 12 months prior to screening or current pneumonitis
• Has an active infection requiring systemic therapy
• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator

Sponsors & Collaborators

• HiberCell, Inc.: lead
• Covance: collaborator

Study Sites (4)

Karmanos Cancer Institute

Detroit, Michigan, 48201, United States

Location

HealthPartners Cancer Care Center

Saint Paul, Minnesota, 55101, United States

Location

Baylor University Medical Center

Dallas, Texas, 75246, United States

Location

The University of Texas M.D. Anderson Cancer Center

Houston, Texas, 77030, United States

Location

MeSH Terms

Conditions

Carcinoma, Renal Cell; Stomach Neoplasms; Breast Neoplasms; Small Cell Lung Carcinoma

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Kidney Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Kidney Diseases; Urologic Diseases; Male Urogenital Diseases; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Stomach Diseases; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Diseases; Respiratory Tract Diseases

Study Officials

• Jose Iglesias, MD

  Consultant Chief Medical Officer for HiberCell, Inc.

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 2, 2021
• First Posted: April 8, 2021
• Study Start: June 8, 2021
• Primary Completion: December 7, 2023
• Study Completion: January 30, 2024
• Last Updated: March 8, 2024

Record last verified: 2024-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (4)