Phase I Trial of PCLX-001 in B-cell Non-Hodgkin Lymphoma and Advanced Solid Malignancies

  • STATUS
    Recruiting
  • End date
    Mar 31, 2023
  • participants needed
    60
  • sponsor
    Pacylex Pharmaceuticals
Updated on 20 September 2021
platelet count
measurable disease
cell transplantation
neutrophil count
beta human chorionic gonadotropin
large b-cell lymphoma

Summary

This is a phase I dose-escalation study of oral PCLX-001, conducted in a multicenter, non-randomized, open-label, non-controlled design. The study is comprised of two parts: Part A (single-agent dose escalation) and Part B (single-agent expansion cohorts).

Description

This is a phase I dose-escalation study of oral PCLX-001, conducted in a multicenter, non-randomized, open-label, non-controlled design. The study is comprised of two parts: Part A (single-agent dose escalation) and Part B (single-agent expansion cohorts).

For Part A dose-escalation, patients will be accrued in cohorts of 3 to 6 patients to each dose level. A new dose level cannot open to accrual until toxicity has been determined in the preceding dose level (i.e. all patients have completed their first cycle of therapy and data for all patients in that dose level have been reviewed at a safety cohort review meeting). Six patients will be treated at the maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D). If required, the MTD cohort may be expanded by an additional 10 patients for further toxicity and response assessment. The MTD cohort expansion may be restricted to B-cell lymphoma or advanced solid tumours to ensure there is proper distribution during dose escalation.

For Part B (single agent expansion cohorts), two expansion cohorts (N=20 each) will be opened to determine the preliminary clinical activity of PCLX-001 at the RP2D:

  • Expansion Cohort A: Participants with advanced solid malignancies showing preclinical sensitivity or molecular markers of sensitivity to PCLX-001. This includes breast, nonsmall cell lung (NSCLC), small-cell lung (SCLC), colorectal (CRC), and bladder cancers
  • Expansion Cohort B: Participants with relapsed/refractory (R/R) B-cell lymphoma: diffuse large B-cell lymphoma (DLBCL), high grade B-cell lymphoma (HGBL), follicular lymphoma (FL), mantle cell lymphoma (MCL), and Burkitt lymphoma. Transformed large B-cell lymphoma will also be included.

Details
Condition B-Cell Lymphoma, Advanced Solid Tumor, Advanced Malignant Solid Tumor
Treatment PCLX-001 treated
Clinical Study IdentifierNCT04836195
SponsorPacylex Pharmaceuticals
Last Modified on20 September 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

Ability to understand and the willingness to sign a written informed consent. A signed informed consent must be obtained before any study-specific procedures are performed
Male or female patients aged 18 years
Dose Escalation
Participants with histologically-confirmed advanced solid tumor who have failed at least one prior therapy and/or are not eligible for therapies expected to provide clinical benefit
Histologically-confirmed B-cell lymphomas that are expected to express CD20 including DLBCL, HGBL, FL (grades 1 to 3b), MCL, and Burkitt lymphoma who have failed at least two prior therapies and/or are not eligible for therapies expected to provide clinical benefit (including autologous stem cell transplantation). Transformed large B-cell lymphoma patients are eligible. FL patients should meet criteria for requiring treatment
Dose Expansion Cohort A: Participants with histologically-confirmed advanced
breast, NSCLC, SCLC, colorectal, and bladder cancers who have failed at least
one prior therapy and/or are not eligible for therapies expected to provide
clinical benefit
Cohort B: Participants with histologically-confirmed R/R B-cell lymphomas that
are expected to express CD20 including DLBCL, HGBL, FL (grades 1-3a), FL
(grade 3b), MCL, and Burkitt lymphoma who have failed at least two prior
therapies and/or are not eligible for therapies expected to provide clinical
benefit. Transformed large B-cell lymphoma patients are eligible. FL patients
should meet criteria for requiring treatment
\. Patients must have evaluable or measurable disease (as per Response
Evaluation Criteria in Solid Tumors, version 1.1 [RECIST 1.1], or the Lugano
lymphoma classification
\. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1
(Appendix A)
\. Life expectancy of at least 12 weeks
\. Patients must have adequate bone marrow function as assessed by the
following laboratory tests to be conducted within 7 (3) days before the first
dose of study
drug
Hemoglobin 85 g/L
Absolute neutrophil count (ANC) 1.5 x 109/L
Platelet count 100 x 109/L for Dose Escalation and 75 x 109/L for Dose Expansion NOTE: For Dose Expansion, patient who do not meet the above hematological criteria, because of bone marrow suppression from prior therapies and/or extensive tumour involvement in the marrow, may be considered for enrollment in the trial after consultation with the Medical Monitor
Patients must have adequate liver function as assessed by the following laboratory tests to be conducted within 7 (3) days before the first dose of study drug
Total bilirubin 1.5 times the upper limit of normal (ULN)
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) 3 times ULN or 5 times ULN for patients with malignant liver involvement
Patients must have adequate kidney function, as assessed by the estimated glomerular filtration rate (eGFR) >50 mL/min within 7 (3) days before the first dose of study drug (eGFR to be calculated by the Cockcroft-Gault formula) or creatinine 1.5 times the ULN
Patients must have adequate coagulation, as assessed by the following laboratory tests to be conducted within 7 (3) days before the first dose of study drug
Prothrombin time/International normalized ratio (PT/INR) 1.5 for patients not on anticoagulation
Activated partial thromboplastin time (aPTT) 1.5 times ULN for patients not on anticoagulation Note: Patients on anticoagulation with an agent such as heparin (eg. enoxaparin, dalteparin, etc.) will be allowed to participate if no prior evidence of underlying abnormality in coagulation parameters exists
Adequate cardiac function per institutional normal measured by echocardiography or multigated acquisition (MUGA) scan (LVEF 50%)
Women of childbearing potential must have a negative serum beta human chorionic gonadotropin (-HCG) pregnancy test obtained within 7 (3) days before the start of administration of study drug
Note: A woman is of childbearing potential, i.e. fertile, following menarche
and until becoming postmenopausal unless permanently sterile. Permanent
sterilization methods include but are not limited to hysterectomy, bilateral
salpingectomy and bilateral oophorectomy. A postmenopausal state is defined as
no menses for 12 months without an alternative medical cause. A high follicle
stimulating hormone (FSH) level in the postmenopausal range may be used to
confirm a postmenopausal state in women not using hormonal contraception or
hormonal replacement therapy
\. Women of childbearing potential and fertile men must agree to use
adequate contraception when sexually active from signing of the informed
consent form for the full study until at least 6 months after the last study
drug administration. Patients must agree to utilize 2 reliable and acceptable
methods of contraception simultaneously. A man is considered fertile after
puberty unless permanently sterile by bilateral orchiectomy. Men being treated
with PCLX-001 are advised not to father a child during and up to 6 months
after treatment; prior to treatment, advice should be sought for conserving
sperm due to the chance of irreversible infertility as a consequence of
treatment with PCLX-001. Female partners of childbearing potential from male
study participants have to use adequate contraception / birth control between
signing of the informed consent and 6 months after the last administration of
the study drug if the male study participant is not sterilized
The investigator or a designated associate is requested to advise the patient
how to achieve highly effective birth control. Highly effective (failure rate
of less than 1% per year) contraception methods, when used consistently and
correctly, include
Combined (estrogen and progestin containing: oral, intravaginal transdermal and progestin-only (oral, injectable, implantable) hormonal contraception associated with inhibition of ovulation
Intra-uterine device (IUD) or intrauterine hormone-releasing system (IUS)
Bilateral tubal occlusion or vasectomized partner (provided that partner is the sole sexual partner and has received medical assessment of the surgical success)
Sexual abstinence (reliability to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient)
Male patients with a female partner of reproductive potential must use a
condom and ensure that an additional form of contraception is also used during
treatment and until 6 months after last study drug administration. Patients
must agree to utilize reliable and acceptable methods of contraception
simultaneously

Exclusion Criteria

Known hypersensitivity to the study drugs or excipients of the preparations or any agent given in association with this study
History of cardiac disease: congestive heart failure New York Heart Association (NYHA) class > II, unstable angina (angina symptoms at rest), new-onset angina (within the past 6 months before study entry), myocardial infarction within the past 6 months before study entry, or uncontrolled cardiac arrhythmias
Uncontrolled arterial hypertension despite optimal medical management (per investigator's opinion)
Moderate or severe hepatic impairment, i.e. Child-Pugh class B or C
Patients with known human immunodeficiency virus (HIV) infection
Patients who have an active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection requiring treatment. Patients with chronic HBV or HCV infection are eligible at the investigator's discretion provided that the disease is stable and sufficiently controlled under treatment
Infections of CTCAE Grade 2 not responding to therapy or active clinically serious infections of CTCAE Grade > 2
Symptomatic metastatic brain or meningeal tumors unless the patient is > 3 months from definitive therapy, has a stable imaging study within 4 weeks prior to the first dose of study drug and is clinically stable with respect to the tumor at the time of study entry. Patients with asymptomatic brain metastases must not be on steroid therapy. Patients with neurological symptoms should undergo a CT / MRI scan of the brain to exclude new or progressive brain metastases
Current or past history of central nervous system (CNS) lymphoma
Uncontrolled seizure disorder requiring therapy (e.g. strong CYP3A4 inducers such as carbamazepine and phenytoin)
History of organ allograft transplantation or autologous stem cell transplantation 3 months prior to the first dose of study drug. Patients who received prior CAR-T or other T-cell targeting treatment (approved or investigational) 4 weeks prior to study drug administration
Evidence or history of bleeding disorder, i.e. any hemorrhage / bleeding event of CTCAE Grade > 2 within 4 weeks before the first dose of study drug
Serious, non-healing wound, ulcer, or bone fracture
Previous or concurrent cancer that is distinct in primary site or histology from the cancer being evaluated in this study, with the exception of the following previous or concurrent cancer types
Curative treatment for localized cancer completed without signs of recurrence and treatment-related toxicity and low risk of recurrence as assessed by the investigator
In-situ prostate cancer, Gleason Score <7, prostate-specific antigen <10 ng/mL (very low risk and low risk, according to therapy guidelines, e.g. the National Comprehensive Cancer Network guideline; active surveillance / observation is a recommended option)
Any clinical condition that is considered unstable or might jeopardize the safety of the patient and his / her compliance in the study
Inability to swallow oral medications
Any malabsorption condition
Breastfeeding. Female patients must not breastfeed during treatment and until 4 months after last study drug administration
Treatment with anticancer chemotherapy or immunotherapy during the study or within 3 weeks before the first dose of study drug. For small-molecule drugs, a period of at least 3 half-lives before the first dose of study drug is acceptable. Mitomycin C or nitrosoureas should not be given within 6 weeks before the first dose of study drug
Treatment with systemic steroids (prednisone dose 10 mg/day or equivalent dose)
Acute toxic effects (CTCAE Grade 2) of previous anticancer chemotherapy or immunotherapy that have not yet stabilized or if significant post-treatment toxicities have been observed. (Note however that toxic effects of previous anticancer therapy considered as chronic, such as chemotherapy-induced neuropathy, fatigue, alopecia, or anorexia of CTCAE Grade <2, for which further resolution is not expected, do not prevent participation in this study.)
Radiotherapy for target lesions during study or within 3 weeks before the first dose of study drug. Palliative radiotherapy is allowed for non-target lesions
Major surgery or significant trauma within 4 weeks before the first dose of study drug
Previous assignment to treatment during this study
Concomitant participation in another clinical study with investigational medicinal product(s)
Substance abuse, medical, psychological, or social conditions that may interfere with the patient's participation in the study or evaluation of the study results
Close affiliation with the investigational site; e.g. a close relative of the investigator, dependent person (e.g. employee or student of the investigational site)
Use of strong CYP3A4 inhibitors and inducers from 14 days prior to first administration of study drug. Strong CYP3A4 inhibitors and inducers are prohibited during the study and until the active FU visit
Clinically relevant findings in the ECG such as a second- or third-degree atrioventricular block, prolongation of the QRS complex > 120 ms (except for bundle branch block pattern), or prolongation of the of the QTc interval (Fridericia) over 450 ms unless agreed otherwise between the investigator and the sponsor's medically responsible person
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