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Brief Title: HC-7366 to Establish the Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D)

A Multicenter, Open-label, Phase 1a/b Study of HC-7366 in Subjects With Advanced Solid Tumors

INTRODUCTION

  • Org Study ID: HC366-FCP2111
  • Secondary ID: N/A
  • NTC ID: NCT05121948
  • Sponsor: HiberCell, Inc.

BRIEF SUMMARY

This is a first in human, multicenter, open label, Phase 1a/b dose escalation and dose expansion study to establish the maximum tolerated dose (MTD), recommended Phase 2 dose (RP2D), and evaluate the safety and tolerability of QD oral dosing of HC 7366 in a dose escalating fashion in subjects with advanced solid tumors. Up to 36 subjects will be enrolled into the Phase 1a dose escalation part of the study. Every effort will be made to ensure approximately 50% of all subjects enrolled in this study will be subjects with the tumors of special interest such as squamous cell carcinoma of the head and neck (SCCHN), colorectal cancer (CRC), non-small cell lung cancer (NSCLC), and transitional cell carcinoma of the bladder (TCC). Subjects with other solid tumor types are also eligible provided study selection criteria are met and they do not exceed 50% of all enrolled subjects. The study will be conducted in the United States at approximately 3 to 5 sites. This Phase 1a/b study will follow a traditional 3+3 design. The starting dose level will be 10 mg QD, escalating to 20, 40, 75, 125, and 150 mg QD as safety allows. All doses are to be administered in the fasting state with water at least 1 hour before food or at least 2 hours after food. The Phase 1b dose expansion part will involve cohort expansion at up to 2 dose levels selected from the dose escalation data by the safety monitoring committee (SMC), to obtain additional safety and preliminary efficacy information. Each cohort in Phase 1b will enroll 15 subjects. The study will be expanded into a Phase 2 study via protocol amendment which will then assess the dose and tumor type(s) selected in Phase 1a/b 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), discontinuation of treatment for other protocol allowed reason (eg, subject refusal), any other administrative reasons, or after 2 years of treatment, whichever occurs first. For scheduling purposes, dosing will occur in 3 week cycles and computed tomography (CT) scans will be conducted once every 6 weeks with the first postbaseline scan after 6 weeks of dosing (precycle 3).

DETAILED DESCRIPTION

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 the first 2 doses: C1D1 and Cycle 1/Day 2 (C1D2) (as local coronavirus disease 19 restrictions allow). 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 and thereafter, on the first day of each cycle for physical and laboratory assessments, adverse event (AE) and dosing compliance monitoring, and PK C3-C6; the End of Treatment visit will also be in person in outpatient clinic. An overnight stay for Cycle 1/Day 21 (C1D21) to C2D1 is optional. Subjects who discontinue before the first postbaseline CT scan for reasons other than disease progression, a treatment-related AE, or dose limiting toxicity (DLT) prior to completion of the DLT evaluation period will be replaced to ensure an adequate safety assessment at each dose level.

Each subject will be treated for a maximum of 2 years and followed for a maximum of 2 years.

Six dose-escalation levels are planned starting with 10 mg QD, escalating to 20, 40, 75, 125, and 150 mg QD. Dose escalation will follow a traditional 3+3 design. A minimum of 3 subjects will be enrolled in each cohort sequentially, with expansion to 6 subjects in each cohort as needed to determine the DLT. For each cohort, the first subject is a sentinel subject. Sentinel subjects will be dosed and followed for 4 days to assess safety and tolerability. If deemed safe and well tolerated, the remainder of the cohort (N=2) will be enrolled. If none of the first 3 subjects in a cohort experiences a study treatment related DLT during the first 21 days (DLT evaluation period), the next cohort may be enrolled. Before applying the dose escalation rules, 3 subjects in a given dose level must have received a minimum of 75% of the planned dose and have been evaluated for toxicity, unless one or more subjects experiences a DLT within the first 21 days. If the first 3 DLT evaluable subjects within a cohort experience no DLTs during the DLT evaluation period, the next cohort may enroll. In the case a subject does not receive a minimum of 75% of the planned dose, for any reason other than a DLT (ie, lost to follow-up), the subject may be replaced. DLT's will be reviewed by the Safety Monitoring Committee (SMC) when the planned number of subjects complete their DLT observation period using the dose-escalation rules. If the MTD is not reached even at the maximum dose level (150 mg QD is well tolerated), a higher dose level may be evaluated based on the SMC recommendations after a comprehensive review of the safety, PK, and efficacy data generated from the study.

  • Overall Status
    Recruiting
  • Start Date
    February 23, 2022
  • Phase
    Phase 1
  • Study Type
    Interventional

PRIMARY OUTCOMES

Primary Outcome 1 - Measure: Determination of MTD of HC-7366

Primary Outcome 1 - Timeframe: Within 18 months of last patient enrolled

Primary Outcome 2 - Measure: Determination of Recommended Phase 2 dose of HC-7366

Primary Outcome 2 - Timeframe: Within 18 months of last patient enrolled

Primary Outcome 3 - Measure: Occurrence of dose-limiting toxicities (DLTs)

Primary Outcome 3 - Timeframe: Within 18 months of last patient enrolled

Primary Outcome 4 - Measure: 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

Primary Outcome 4 - Timeframe: Within 18 months of last patient enrolled

Primary Outcome 5 - Measure: Incidence of TEAEs leading to premature discontinuation

Primary Outcome 5 - Timeframe: Within 18 months of last patient enrolled

Primary Outcome 6 - Measure: Incidence of laboratory abnormalities, based on NCI CTCAE grades of hematology, serum chemistry, and urinalysis test results

Primary Outcome 6 - Timeframe: Within 18 months of last patient enrolled

Primary Outcome 7 - Measure: Incidence of abnormalities observed in 12 lead ECG parameters

Primary Outcome 7 - Timeframe: Within 18 months of last patient enrolled

Primary Outcome 8 - Measure: Incidence of abnormalities observed in vital signs measurements

Primary Outcome 8 - Timeframe: Within 18 months of last patient enrolled

CONDITION

  • Squamous Cell Carcinoma of Head and Neck
  • Colo-rectal Cancer
  • Non Small Cell Lung Cancer
  • Transitional Cell Carcinoma of the Bladder
  • Other Solid Tumors

ELIGIBILITY

Inclusion Criteria:
Have a signed an 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 tumor types with qualifying characteristics, and have received at least 1 and no more than 5 prior lines of therapy:
SCCHN

- CRC

- NSCLC

- TCC

- Other solid tumors (eg, carcinoma of unknown primary) with the exception of rapidly progressing neoplasms (eg, pancreatic cancer, glioblastoma, hepatocellular carcinoma). Note: Subjects do not need to have progressed through all possible available therapies with known clinical benefit for their respective cancers to participate in this study. Note: Subjects with SCCHN, CRC, NSCLC, and TCC are a priority and should constitute as a whole, at least 50% of the enrolled population. Enrollment of all others will be capped when reaching a combined 50%, in order to maintain 18 slots for subjects with SCCHN, CRC, NSCLC, and TCC.

- Have at least 1 radiologically measurable lesion as per Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1 defined as a lesion that is at least 10 mm in longest diameter or lymph node that is at least 15 mm in short axis imaged by CT scan or magnetic resonance imaging and obtained by imaging within 28 days prior to study treatment. 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

- If subjects were previously treated with immune checkpoint inhibitors, at least 4 weeks must have elapsed since the last dose, and toxicities resolved as above

- Subjects must have at least one biopsiable lesion at baseline. Biopsies in this clinical study will conform to American Society of Clinical Oncology's Ethical Framework for Including Research Biopsies in Oncology Clinical Trials. Provided there are suitable and accessible lesions, no biopsy contraindications, minimal risk of complications and a positive informed decision, subjects 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 15 days prior to study Day 1) and at the time of the first response assessment CT scan at Cycle 3/Day 1 (+7 days). Newly obtained biopsy specimens are preferred to archived samples and formalin fixed, paraffin embedded block specimens are preferred to slides

- Have Eastern Cooperative Oncology Group performance status of 0 or 1 and sustained between screening and initiation of dosing on Day 1

- Have no swallowing difficulties that would prevent compliance with oral dosing

- Have not experienced >10% body weight loss in the previous 4 weeks

- Have a serum albumin level >3 g/dL

- Have life expectancy of 3 months or greater as determined by the treating physician
Have adequate organ function on Day 1, as defined by meeting all of the following criteria:
Total bilirubin ≤1.5 × upper limit of normal (ULN) OR direct bilirubin ≤ULN for subjects with total bilirubin levels >1.5 x ULN

- Aspartate aminotransferase and alanine aminotransferase ≤2.5 × ULN or ≤5 × ULN for subjects with known hepatic metastases

- Have adequate renal function on Day 1, as defined by creatinine ≤1.5 × ULN and creatinine clearance ≥60 mL/min, as per the below Cockcroft Gault formula
Have adequate hematologic function on Day 1, as defined by meeting all of the following criteria:
Hemoglobin ≥9 g/dL (uncorrected by red blood cell transfusion or erythropoietin support)

- Absolute neutrophil count ≥1.5 × 109/L

- Platelet count ≥100 × 109/L
Have adequate coagulation function on Day 1, as defined by either of the following criteria:
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 - Activated partial thromboplastin time <1.5 × ULN unless subject is receiving anticoagulant therapy, provided prothrombin time or partial thromboplastin time is within therapeutic range of intended use of anticoagulants - Have normal or adequately controlled pan-endocrine function (pituitary, adrenal, thyroid, pancreatic, gonadal). Subjects on hormonal supplementation must be stable at their treatment doses - Female subjects of childbearing potential must have a negative urine or serum pregnancy test 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 - Female subjects of childbearing potential must be willing to use an adequate form of contraception from the signing of the ICF until 90 days after the last dose of study medication - Female subjects must agree not to breastfeed and not to donate ova starting at screening and throughout the study treatment, and for 90 days after the final administration of study drug - Male subjects 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 their partner is breastfeeding throughout the study treatment and for 90 days after the final administration of study drug - Male subjects must not donate sperm during the treatment period and for at least 90 days after the final administration of the study drug - Male subjects with female partner(s) of child bearing potential must agree to use a condom with spermicide during the treatment period and for at least 90 days after the final administration of the study drug - Be willing and have the ability to comply with scheduled visits (including geographical proximity), treatment plans, laboratory tests, and other study procedures.
Exclusion Criteria:
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 may be approved after consultation with the sponsor

- Has known history of active tuberculosis

- Has known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)

- Has known active hepatitis B (eg, hepatitis B surface antigen reactive) or hepatitis C (eg, hepatitis C virus ribonucleic acid [RNA] [qualitative]) infection

- Has been diagnosed with severe acute respiratory syndrome coronavirus 2 infection confirmed by real time polymerase chain reaction (PCR) test as per the local guidelines at screening and positive by PCR within 7 days prior to the first dose of study treatment

- Has a history of clinically severe autoimmune disease, or history of organ transplant

- Has a history of retinitis or photosensitive skin disorders including (but not limited to) erythema multiforme, atopic eczema, psoriasis, viral exanthemata, pemphigus, and dermatitis herpetiformis

- Has known additional malignancy that is progressing or required active treatment within the 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 study 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 study 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 study, interfere with the subject's participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator

- Has a clinically significant cardiovascular disease such as unstable angina, myocardial infarction, or acute coronary syndrome, symptomatic or uncontrolled arrhythmia, congestive heart failure, baseline electrocardiogram (ECG) abnormalities, including, but not limited to, QTc prolongation to greater than 470 ms, or any Class III or IV cardiac disease as defined by the New York Heart Association Functional Classification

- 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

- Has a known psychiatric or substance abuse disorder(s) that would interfere with informed consent or cooperation with the requirements of the study

- Is pregnant or breastfeeding or expecting to conceive children within the projected duration of the study, starting with the screening visit through 90 days after the final administration of the study drug

- Is a first degree relative of the investigator, staff, or study sponsor.

Gender: All

Minimum Age: 18 Years

Maximum Age: N/A

Healthy Volunteers: No

OFFICIAL INFORMATION

Name: Jose Iglesias, MD

Role: Study Director

Affiliation: Consultant Chief Medical Officer for HiberCell, Inc.

Overall Contact

Name: Jose Iglesias, MD

Phone: 708-295-1226, 816-260-2097

Email: viviana.cecinato@labcorp.com, holly.brems@labcorp.com

LOCATION

Facility Status Contact
Facility: University of Colorado Anschutz Medical Campus
Aurora, Colorado 80045
United States
Status: Recruiting Contact: Contact
Sunnie Kim, MD
303-724-2520
Sunnie.Kim@CUAnschutz.edu
Facility: Sarah Cannon Research Institute /Tennessee Oncology
Nashville, Tennessee 37203
United States
Status: Recruiting Contact: Contact
Mark Morrow
720-848-0665
mark.morrow@ucdenver.edu
Facility: The University of Texas M.D. Anderson Cancer Center
Houston, Texas 77030
United States
Status: Recruiting Contact: Contact
Meredith Pelster, MD
(615) 524-4986
meredith.pelster@sarahcannon.com