Study of PCLX-001 in R/R Advanced Solid Malignancies and B-cell Lymphoma

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

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).

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 enrolled 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.

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.

5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.

6. Life expectancy of at least 12 weeks

7. Patients must have adequate bone marrow, liver, kidney and cardiac function.

8. Patients must have adequate coagulation.

9. Women of childbearing potential must have a negative pregnancy test.

10. 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.

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.
4. Moderate or severe hepatic impairment.
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.
7. Infections not responding to therapy or active clinically serious infections.
8. Symptomatic metastatic brain or meningeal tumors unless the patient is > 3 months from definitive therapy, has a stable imaging study and is clinically stable. Patients with asymptomatic brain metastases must not be on steroid therapy.
9. Current or past history of central nervous system (CNS) lymphoma.
10. Uncontrolled seizure disorder requiring therapy.
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 within 4 weeks before the first dose of study drug.
13. Serious, non-healing wound, ulcer, or bone fracture.
14. Any malabsorption condition.
15. Breastfeeding. Female patients must not breastfeed during treatment and until 4 months after last study drug administration.
16. Treatment with systemic steroids (prednisone dose ≥10 mg/day or equivalent dose).
17. Acute toxic effects of previous anticancer chemotherapy or immunotherapy that have not yet stabilized or if significant post-treatment toxicities have been observed.
18. Radiotherapy for target lesions during study or within 3 weeks before the first dose of study drug.
19. Major surgery or significant trauma within 4 weeks before the first dose of study drug.
20. Concomitant participation in another clinical study with investigational medicinal product(s).
21. Substance abuse, medical, psychological, or social conditions that may interfere with the patient's participation in the study or evaluation of the study results.
22. 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 follow up visit.
23. Clinically relevant findings in the ECG.