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

• ClinicalTrials.gov Identifier: NCT04836195
• Recruitment Status: Recruiting
• First Posted: April 8, 2021
• Last Update Posted: September 27, 2022
• Sponsor: Pacylex Pharmaceuticals
• Collaborator: Ozmosis Research Inc.
• Information provided by (Responsible Party): Pacylex Pharmaceuticals

Study Description

Brief 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).

Condition or disease	Intervention/treatment	Phase
B-cell Non Hodgkin Lymphoma; Advanced Solid Tumor	Drug: PCLX-001 treated	Phase 1

Detailed 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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 60 participants
• Allocation: N/A
• Intervention Model: Sequential Assignment
• Intervention Model Description: 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).
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase I Trial of PCLX-001 in Relapsed/Refractory B-cell Non-Hodgkin Lymphoma and Advanced Solid Malignancies
• Actual Study Start Date: September 14, 2021
• Estimated Primary Completion Date: February 28, 2023
• Estimated Study Completion Date: July 31, 2023

Arms and Interventions

Arm

Intervention/treatment

Experimental: PCLX-001 intervention; The Dose-Escalation phase will follow a standard 3+3 cohort design. Three patients will be treated at each dose level. If 0/3 patients experience DLT, 3 patients will be treated at the next dose level. Escalation will terminate as soon as two or more patients experience any DLT attributable to study drugs, at a given dose level. Oral PCLX-001 will be provided as continuous daily dosing on a 28-day cycle. The starting dose of PCLX-001 will be 20 mg daily Expansion Cohort Once the MTD has been defined, preliminary activity will be further evaluated in the expansion part of the study. The RP2D may be the MTD but not necessarily as not only safety data will be taken into account prior to its determination.

Drug: PCLX-001 treated; To ensure maximal safety in this first-in-human trial, the starting dose level was chosen to be 20 mg daily. PCLX-001 will be provided as an oral flat daily dose on a 28-day cycle. Missed doses for any reason will not be administered at a later time. The Dose-Escalation phase will follow a standard 3+3 cohort design. Three patients will be treated at each dose level. If 0/3 patients experience DLT, 3 patients will be treated at the next dose level. If DLT attributable to the treatment is experienced in 1/3 patients, three more patients (for a total of six patients) will be treated at that dose level. If no additional DLT is observed at the expanded dose level (i.e. 1/6 with DLT), the dose will be escalated. Escalation will terminate as soon as two or more patients experience any DLT attributable to study drugs, at a given dose level. DLT and determination of MTD will be based on cycle 1 toxicities.

Outcome Measures

Primary Outcome Measures :

1. To determine, during the dose escalation phase, the recommended dose of PCLX-001 for the dose expansion phase of the trial. [ Time Frame: Cycle length is 28 days ]
   The recommended dose will be the dose level below that for the cohort in which maximum tolerated dose (MTD) was reached/exceeded. MTD will have been reached when 2 or more patients in a cohort experience DLT.
2. To determine the time to maximum plasma level (Tmax) of PCLX-001 [ Time Frame: Measured on Cycle 1: Pre-dose on Days 1,2,8(±2), 15 (±2), 22 (±2), Day 1 and Day 15 will also measure at 0.5 hour, 1 hour, 2 hours, 4 hours, 8 hours; Cycle 2 pre-dose on Day 1 & 15; Cycle 3 pre-dose on Day 1 (Each cycle is 28 days) ]
   Tmax is the time at which the maximum plasma concentration of PCLX-001 is achieved.
3. To determine the maximum plasma level (Cmax) of PCLX-001 [ Time Frame: Measured on Cycle 1: Pre-dose on Days 1,2,8(±2), 15 (±2), 22 (±2), Day 1 and Day 15 will also measure at 0.5 hour, 1 hour, 2 hours, 4 hours, 8 hours; Cycle 2 pre-dose on Day 1 & 15; Cycle 3 pre-dose on Day 1 (Each cycle is 28 days) ]
   Cmax is the maximum plasma concentration of PCLX-001.

Secondary Outcome Measures :

1. To evaluate the clinical response rate in patients treated with PCLX-001 with advanced solid malignancies [ Time Frame: Tumor measurements for efficacy evaluation will be made at initiation and at the end of every 2nd cycle (each cycle is 28 days) ]
   Tumor response and progression of solid tumors and NHL will be evaluated by the investigator at each study center consistent with RECIST 1.1 criteria.
2. To evaluate the clinical response rate in patients treated with PCLX-001 with relapsed/refractory (R/R) B-cell lymphoma [ Time Frame: Tumour assessment will be done at the end of every second cycle (each cycle is 28 days). ]
   Tumor response and progression of solid tumors and NHL will be evaluated by the investigator at each study center consistent with Lugano Classification of Lymphoma response.

Other Outcome Measures:

1. Assess the pharmacodynamic (PD) effects of PCLX-001 in patients with B-cell lymphomas [ Time Frame: Cycle 1 Days 1, 2, 8, 15, 22; Cycle 2 Days 1 & 15, Cycle ≥ 3 Day 1 (Cycle is 28 days) ]
   Collection of blood samples for exploratory biomarker research is also a part of this trial. Specimens will be stored and may be used for research purposes to identify biomarkers useful for predicting and monitoring PCLX-001.
2. Assess the pharmacodynamic (PD) effects of PCLX-001 in patients with advanced solid tumours [ Time Frame: Access either archived biopsies or at patient screening ]
   Archived tissue samples will be requested from all patients and pre-treatment biopsies will be optional for patients enrolled in whom an archival biopsy is older than 6 months. These will be collected for response prediction analyses and exploratory research. Archived tumour blocks will be returned to the clinical investigator at the end of the study or, if requested, once sections have been obtained for biomarker analysis.

Eligibility Criteria

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

Criteria

Inclusion Criteria:

1. 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.
2. Male or female patients aged ≥ 18 years

3. Dose Escalation

   1. 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.
   2. 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.

4. 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.
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 (Appendix A).
6. Life expectancy of at least 12 weeks

7. 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:

   1. Hemoglobin ≥ 85 g/L
   2. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
   3. 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.

8. 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:

   1. Total bilirubin ≤ 1.5 times the upper limit of normal (ULN)
   2. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 times ULN or ≤ 5 times ULN for patients with malignant liver involvement
9. 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

10. 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:

    1. Prothrombin time/International normalized ratio (PT/INR) ≤ 1.5 for patients not on anticoagulation
    2. 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.
11. Adequate cardiac function per institutional normal measured by echocardiography or multigated acquisition (MUGA) scan (LVEF ≥ 50%)

12. Women of childbearing potential must have a negative serum beta human chorionic gonadotropin (β-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.

13. 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:

1. Known hypersensitivity to the study drugs or excipients of the preparations or any agent given in association with this study
2. 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
3. Uncontrolled arterial hypertension despite optimal medical management (per investigator's opinion)
4. Moderate or severe hepatic impairment, i.e. Child-Pugh class B or C
5. Patients with known human immunodeficiency virus (HIV) infection
6. 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.
7. Infections of CTCAE Grade 2 not responding to therapy or active clinically serious infections of CTCAE Grade > 2
8. 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.
9. Current or past history of central nervous system (CNS) lymphoma
10. Uncontrolled seizure disorder requiring therapy (e.g. strong CYP3A4 inducers such as carbamazepine and phenytoin)
11. 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
12. 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
13. Serious, non-healing wound, ulcer, or bone fracture

14. 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).
15. Any clinical condition that is considered unstable or might jeopardize the safety of the patient and his / her compliance in the study
16. Inability to swallow oral medications
17. Any malabsorption condition
18. Breastfeeding. Female patients must not breastfeed during treatment and until 4 months after last study drug administration.
19. 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.
20. Treatment with systemic steroids (prednisone dose ≥10 mg/day or equivalent dose).
21. 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.)
22. 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.
23. Major surgery or significant trauma within 4 weeks before the first dose of study drug
24. Previous assignment to treatment during this study
25. Concomitant participation in another clinical study with investigational medicinal product(s)
26. Substance abuse, medical, psychological, or social conditions that may interfere with the patient's participation in the study or evaluation of the study results
27. 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)
28. 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.
29. 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

Contacts and Locations

Contacts

Contact: Pacylex; 1 (888) 580-4483; info@pacylex.com

Locations

Canada, Alberta

Cross Cancer Institute; Recruiting

Edmonton, Alberta, Canada, T6G 1Z2

Contact: Randeep Sangha info@pacylex.com

Principal Investigator: Randeep Sangha, MD

Canada, Ontario

Princess Margaret Hospital; Recruiting

Toronto, Ontario, Canada, M5G 2M9

Contact: Swati Singla, M Sc 416-946-4501 ext 5742 CCRUkitsquad@uhn.ca

Principal Investigator: John Kuruvilla, MD

Canada, Quebec

Centre Hospitalier de l'Université de Montréal - CHUM; Recruiting

Montréal, Quebec, Canada, H2X 0C1

Contact: Adeline Hamon 514-890-8000 ext 30737 uit.eligibilite.chum@ssss.gouv.qc.ca

Sponsors and Collaborators

Pacylex Pharmaceuticals

Ozmosis Research Inc.

Investigators

• Principal Investigator: Randeep Sangha; Cross Cancer Institute

More Information

Study Data/Documents: Study Protocol 

Informed Consent Form 

Publications:

Beauchamp E, Yap MC, Iyer A, Perinpanayagam MA, Gamma JM, Vincent KM, Lakshmanan M, Raju A, Tergaonkar V, Tan SY, Lim ST, Dong WF, Postovit LM, Read KD, Gray DW, Wyatt PG, Mackey JR, Berthiaume LG. Targeting N-myristoylation for therapy of B-cell lymphomas. Nat Commun. 2020 Oct 22;11(1):5348. doi: 10.1038/s41467-020-18998-1.

• Responsible Party: Pacylex Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT04836195
• Other Study ID Numbers: PCLX-001-01
• First Posted: April 8, 2021
• Last Update Posted: September 27, 2022
• Last Verified: September 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Lymphoma; Lymphoma, Non-Hodgkin; Lymphoma, B-Cell; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases