Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04834778
Recruitment Status : Recruiting
First Posted : April 8, 2021
Last Update Posted : August 2, 2021
Sponsor:
Collaborator:
Covance
Information provided by (Responsible Party):
HiberCell, Inc.

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 24 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. If MTD is not reached even at the maximum dose level (200 mg BID is well tolerated), a higher dose level may be evaluated based on the safety monitoring committee (SMC) recommendations after a comprehensive review of the PK, safety, and efficacy data generated from the study. 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.

Condition or disease Intervention/treatment Phase
Renal Cell Carcinoma Gastric Cancer Metastatic Breast Cancer Small-cell Lung Cancer Other Solid Tumors Drug: HC-5404-FU Phase 1

Detailed Description:

HC 5404-FU will be orally administered BID with food or within 30 minutes of completing a meal, starting at 25 mg, with doses escalating to 50, 100, and 200 mg BID as safety allows. Up to 24 subjects will be enrolled to ensure 12 subjects complete the study at the estimated MTD of HC 5404-FU. Dosing will occur in 3-week cycles. Subjects are to spend Cycle 1/Day 1 (C1D1) in the clinic followed by an overnight stay for safety monitoring and PK sampling. Subjects will be hospitalized for administration of first 3 doses: C1D1 am and pm doses, and Cycle 1/Day 2 (C1D2) am dose; on Days 8, 15, and 21 the am dose will be taken in the clinic after the planned PK samples. All other doses are to be self administered at home. After the initial hospital stay at the start of study, subjects will be seen in outpatient clinic on Days 8, 15, and 21 of Cycle 1 for PK assessment and thereafter, the first day of each cycle for physical and laboratory assessments, adverse event (AE), and dosing compliance monitoring; the end of treatment visit will also be in person in outpatient clinic.

Following completion of the treatment period of the study, subjects will be monitored for survival up for up to 24 months after the last post treatment follow-up visit.

Dose escalation will follow the Bayesian Optimal Interval (BOIN) design. The decision to escalate to the next dose level will be based on safety assessments after all subjects of a cohort have reached the end of Cycle 1/Day 21 (DLT evaluation period). The safety monitoring committee (SMC) will be responsible for dose escalation decisions, including whether to modify the dose escalation based on the DLT observations and review of available PK data.

The target toxicity rate of 30%, with limits of 0.236 to 0.359 for escalation/de escalation, will be employed to determine the MTD. With these predefined parameters, when the observed toxicity rate in a dose level is less than 0.236, the dose for the next cohort can escalate. If the observed toxicity rate is higher than 0.359, the dose will de escalate. Otherwise, the dose remains the same.

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 24 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Multicenter, Open-label, Phase 1a Study of HC-5404-FU in Subjects With Advanced Solid Tumors
Actual Study Start Date : June 8, 2021
Estimated Primary Completion Date : March 2022
Estimated Study Completion Date : April 2022


Arm Intervention/treatment
Experimental: Cohort 1 - 25 mg
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
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, and 200 mg BID as safety allows for each 3-week treatment cycle.
Other Name: HC-5404

Experimental: Cohort 2 - 50 mg
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
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, and 200 mg BID as safety allows for each 3-week treatment cycle.
Other Name: HC-5404

Experimental: Cohort 3 - 100 mg
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
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, and 200 mg BID as safety allows for each 3-week treatment cycle.
Other Name: HC-5404

Experimental: Cohort 4 - 200 mg
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
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, and 200 mg BID as safety allows for each 3-week treatment cycle.
Other Name: HC-5404




Primary Outcome Measures :
  1. Determination of MTD of HC-5404-FU [ Time Frame: Within 18 months of last patient enrolled ]
    When orally administered in a dose escalating fashion in subjects with selected, advanced solid tumors

  2. Occurrence of dose-limiting toxicities (DLTs) [ Time Frame: Within 18 months of last patient enrolled ]
  3. 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 [ Time Frame: Within 18 months of last patient enrolled ]
  4. Incidence of TEAEs leading to premature discontinuation [ Time Frame: Within 18 months of last patient enrolled ]
  5. Incidence of significant laboratory abnormalities, based on hematology, serum chemistry, and urinalysis test results [ Time Frame: Within 18 months of last patient enrolled ]
  6. Incidence of abnormalities observed in 12 lead ECG parameters [ Time Frame: Within 18 months of last patient enrolled ]
  7. Incidence of abnormalities observed in vital signs measurements and physical examinations [ Time Frame: Within 18 months of last patient enrolled ]

Secondary Outcome Measures :
  1. Area under the plasma concentration versus time curve from time 0 until last measurable concentration (AUC0 last) [ Time Frame: Within 24 months of last patient enrolled ]
  2. Area under the plasma concentration versus time curve from time 0 to 12 hours postdose (AUC0 12) [ Time Frame: Within 24 months of last patient enrolled ]
  3. Area under the plasma concentration versus time curve from time 0 extrapolated to infinity (AUC0 ∞) [ Time Frame: Within 24 months of last patient enrolled ]
  4. Area under the plasma concentration versus time curve over a dosing interval (AUC0 t) [ Time Frame: Within 24 months of last patient enrolled ]
  5. Peak plasma concentration (Cmax) [ Time Frame: Within 24 months of last patient enrolled ]
  6. Time of the maximum observed plasma concentration (tmax) [ Time Frame: Within 24 months of last patient enrolled ]
  7. Apparent total clearance (CL/F) of plasma concentration [ Time Frame: Within 24 months of last patient enrolled ]
  8. Apparent volume of distribution during the terminal phase (Vz/F) of plasma concentration [ Time Frame: Within 24 months of last patient enrolled ]
  9. Apparent terminal elimination half life (t1/2) of plasma concentration [ Time Frame: Within 24 months of last patient enrolled ]
  10. Accumulation ratio based on AUC0 t (ARAUC) of plasma concentration [ Time Frame: Within 24 months of last patient enrolled ]
  11. Linearity ratio (LR) of plasma concentration [ Time Frame: Within 24 months of last patient enrolled ]
  12. Overall response rate (ORR) to HC-5404-FU using iRECIST [ Time Frame: Within 24 months of last patient enrolled ]
  13. Duration of response (DOR) to HC-5404-FU using iRECIST [ Time Frame: Within 24 months of last patient enrolled ]
  14. Time to treatment failure (TTF) [ Time Frame: Within 24 months of last patient enrolled ]
  15. Progression-free survival (PFS) using iRECIST [ Time Frame: Within 24 months of last patient enrolled ]
  16. Overall response (OS) using iRECIST [ Time Frame: Within 24 months of last patient enrolled ]


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.


Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Have a signed informed consent form prior to any study specific procedures or treatment
  2. Be ≥18 years of age (male or female) at the time of consent
  3. 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:

    1. RCC (renal cell carcinoma - clear cell or papillary)
    2. 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:
    3. GC (gastric adenocarcinoma)
    4. Human epidermal growth factor receptor positive (HER2+) MBC (metastatic breast cancer)
    5. 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 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.

  4. 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
  5. 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
  6. 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

  7. Have Eastern Cooperative Oncology Group performance status of 0 or 1 and sustained between screening and initiation of dosing on Day 1
  8. QT interval corrected for heart rate using Fridericia's (QTcF) method ≤450 msec
  9. Have an albumin level of ≥3 g/dL at screening
  10. Have life expectancy of 3 months or greater as determined by the treating physician
  11. Have adequate organ function within 15 days prior to first administration of study drug on Day 1, as defined by meeting all of the following criteria:

    1. Total bilirubin ≤1.5 × upper limit of normal (ULN) OR direct bilirubin ≤ ULN for subjects with total bilirubin levels >1.5 x ULN
    2. Aspartate aminotransferase and alanine aminotransferase ≤2.5 × ULN or ≤5 × ULN for subjects with known hepatic metastases
    3. Fasting serum glucose within normal range and hemoglobin A1c ≤8%
    4. Thyroid function tests (thyroid stimulating hormone [TSH] within normal limits for subjects with normal thyroid function and free thyroxine [FT4]) within normal limits for subjects on thyroid treatment
  12. Have adequate renal function within 15 days prior to first administration of study drug on Day 1, as defined by creatinine ≤1.5 × ULN and creatinine clearance ≥30 mL/min, as per the below Cockcroft Gault formula
  13. Have adequate hematologic function within 15 days prior to first administration of study drug on Day 1, as defined by meeting all of the following criteria:

    1. Hemoglobin ≥9 g/dL (uncorrected by red blood cell transfusion or erythropoietin support)
    2. Absolute neutrophil count ≥1.5 × 109/L
    3. Platelet count ≥100 × 109/L
  14. Have adequate coagulation function within 15 days prior to first administration of study drug on Day 1, as defined by either of the following criteria:

    1. International normalized ratio (INR) <1.5 × ULN OR for subjects receiving warfarin or low molecular weight heparin, the subject must, in the investigator's opinion, be clinically stable with no evidence of active bleeding while receiving anticoagulant therapy. The INR for these subjects may exceed 1.5 × ULN if that is the goal of anticoagulant therapy
    2. Activated partial thromboplastin time (aPTT) <1.5 × ULN unless subject is receiving anticoagulant therapy, provided prothrombin time or aPTT is within therapeutic range of intended use of anticoagulants
  15. Female subject of childbearing potential must have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
  16. Female subject of childbearing potential must be willing to use an adequate form of contraception from the first dose of study medication through 90 days after the last dose of study drug
  17. Female subject must agree not to breastfeed and not to donate ova starting at screening and throughout the study treatment, and for 90 days after the last dose of study drug
  18. Male subject with a pregnant or breastfeeding partner(s) must agree to remain abstinent or use a condom for the duration of the pregnancy or for the time partner is breastfeeding throughout the study period and for 90 days after the last dose of study drug
  19. Male subject with female partner(s) of childbearing potential must not donate sperm during the treatment period and for at least 90 days after the last dose of study drug
  20. Male subject with female partner(s) of childbearing potential should agree to use a highly effective method of contraception during the treatment period and for at least 90 days after the last dose of the study drug
  21. Be willing and have the ability to comply with scheduled visits (including geographical proximity), treatment plans, laboratory tests, and other study procedures.

Exclusion Criteria:

  1. 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
  2. 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
  3. 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
  4. Has taken a medication that is a strong CYP3A4 inhibitor or inducer within 4 weeks of the first dose of treatment (see Appendix 12)
  5. Has known history of active tuberculosis
  6. Has known history of HIV (HIV 1/2 antibodies)
  7. 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
  8. 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
  9. Has a history of clinically severe autoimmune disease, or a history of organ transplant
  10. Has insulin dependent (Type I) diabetes or poorly controlled Type II diabetes (per clinical discretion) with hemoglobin A1c >8%
  11. 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
  12. 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
  13. Has a history of interstitial lung disease, pneumonitis within 12 months prior to screening or current pneumonitis
  14. Has an active infection requiring systemic therapy
  15. 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
  16. Has a history or ongoing clinically significant cardiovascular disease such as unstable angina, myocardial infarction, or acute coronary syndrome, symptomatic or uncontrolled arrhythmia, congestive heart failure, baseline ECG abnormalities, including, but not limited to, QTc prolongation (prolonged QTcF defined as ≥450 msec) or any Class III or IV cardiac disease as defined by the New York Heart Association Functional Classification
  17. Has overt or latent disorders of the exocrine pancreas (such as acute or chronic pancreatitis of any etiology) or chronic (including autoimmune) gastrointestinal disorders such as Crohn's disease, ulcerative colitis, rheumatoid arthritis, lupus, scleroderma, Sjogren's syndrome, and polyarteritis nodosa
  18. Has a known psychiatric or substance abuse disorder(s) that would interfere with informed consent or cooperation with the requirements of the trial
  19. Is pregnant or breastfeeding or expecting to conceive children within the projected duration of the trial, starting with the prescreening or screening visit through 90 days after the last dose of study drug
  20. Is a first degree relative of the investigator, staff, or study sponsor.

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): NCT04834778


Contacts
Layout table for location contacts
Contact: Viviana Cecinato, MPharm 708-295-1226 Viviana.Cecinato@covance.com
Contact: Matthew Barnes Matthew.Barnes@covance.com

Locations
Layout table for location information
United States, Minnesota
HealthPartners Cancer Care Center Recruiting
Saint Paul, Minnesota, United States, 55101
Contact: Jacquelyn Christenson    651-254-3602    Jacquelyn.christenson@parknicollet.com   
Contact: Octav Pacurar    651-254-3604    octav.pacurar@parknicollet.com   
Principal Investigator: Arkadiusz Dudek, MD, PhD         
United States, Texas
The University of Texas M.D. Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Katrien Van Roosbroeck    713-563-1055    kvan1@mdanderson.org   
Contact: Rabia Khan    (713) 563-4667    rkhan@mdanderson.org   
Principal Investigator: Sarina Piha-Paul, MD         
Sponsors and Collaborators
HiberCell, Inc.
Covance
Investigators
Layout table for investigator information
Study Director: Jose Iglesias, MD Consultant Chief Medical Officer for HiberCell, Inc.
Layout table for additonal information
Responsible Party: HiberCell, Inc.
ClinicalTrials.gov Identifier: NCT04834778    
Other Study ID Numbers: HC-404-FCP-2011
First Posted: April 8, 2021    Key Record Dates
Last Update Posted: August 2, 2021
Last Verified: July 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by HiberCell, Inc.:
RCC
GC
MCA
SCLC
Phase 1
First in human
HC-5404-FU
HC-5404
Additional relevant MeSH terms:
Layout table for MeSH terms
Carcinoma, Renal Cell
Small Cell Lung Carcinoma
Neoplasms by Site
Neoplasms
Adenocarcinoma
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Kidney Neoplasms
Urologic Neoplasms
Urogenital Neoplasms
Kidney Diseases
Urologic Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms
Lung Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Lung Diseases
Respiratory Tract Diseases