A Phase 1, Open-Label Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Preliminary Efficacy of HMPL-689 in Patients with Relapsed or Refractory Lymphoma
- Signed informed consent form (ICF)
- Age 18 years
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1;
- Histologically confirmed NHL of the following sub-types CLL/SLL, FL (grade 1-3a), MCL, MZL, LPL/WM, PTCL or CBCL;
- Patients with CLL/SLL, FL (grade 1-3a), MCL and LPL/WM must have received at least 2 prior lines of systemic therapy.
- Patients with MZL must have received at least 1 prior line of systemic therapy that includes an anti-CD20 monoclonal antibody agent.
- Patients with PTCL and CBCL must have received at least 1 prior line of systemic therapy.
- Patients with relapsed, refractory, or resistant NHL, as defined below:
- Refractory to any prior regimen, defined as no response (complete response or partial response) to previous therapies, or progression within 6 months of completion of the last dose of prior therapy.
- Those who can no longer tolerate/withstand cytotoxic chemotherapy and/or available standard of treatment/care (SoT/SoC), where safety profile and risks of toxicity of other treatment options far outweigh any possible clinical benefit.
- Those with no curative SoT or no reasonable access to available treatments, in particular, those who will benefit from this class of compound, in the opinion of the attending investigator.
- In the dose expansion stage, patients must have measurable disease for an objective response assessment, except for patients with CLL and WM/LPL. NOTE: Measurable disease with FL, MCL, MZL, PTCL, CBCL, or SLL is defined as at least 1 bi-dimensionally measurable lesion (>1.5 cm in its largest dimension by computerized tomography [CT] scan).
- Expected survival of more than 24 weeks as determined by the principal investigator.
- Patients with prior treatment with any PI3K? inhibitors are eligible for dose escalation. However, during dose expansion, only patients that discontinued PI3K? inhibitor for reasons other than disease progression are eligible.
- Male patients must agree to use a condom and female patients of childbearing potential must agree to use highly effective contraceptive measures that result in a low failure rate (<1% per year) when used consistently and correctly, from the screening period, through the entire study period, and for 30 days after the last dose of study drug. These highly effective contraceptive measures, as defined by the Clinical Trials Facilitation Group (CTFG)*, include combined estrogen and progestogen hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal), progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable), intrauterine device or intrauterine hormone-releasing system, bilateral tubal occlusion, a vasectomized partner, or sexual abstinence if in the preferred and usual lifestyle of the patient. These same criteria are applicable to partners of patients involved in this clinical study if that partner is of childbearing potential. Postmenopausal females (no menses for 12 months without an alternative medical cause) and surgically sterilized females are exempt from this criterion.
- Patients with primary central nervous system (CNS) lymphoma.
- Any of the following laboratory abnormalities:
- Absolute neutrophil count 1.0 × 109/L
- Hemoglobin 80 g/L
- Platelets < 50 × 109/L
- Inadequate organ function, defined by the following:
• Total bilirubin 1.5 times the upper limit of normal (× ULN), with the following exception
– Patients with known Gilbert’s disease who have serum total and direct bilirubin level 2.5 ULN and normal aspartate transaminase (AST) and alanine transaminase (ALT) can be enrolled.
• AST or ALT 2.5 ULN, with the following exception:
− In the dose expansion stage, patients with documented disease infiltration of the liver may have AST and ALT levels 5 ULN.
• Estimated creatinine clearance (CrCl) per Cockcroft-Gault
− Dose escalation stage of trial (Stage 1) – CrCl <40 mL/min
− Dose expansion stage of trial (Stage 2) – CrCl <30 mL/min
4. International normalized ratio (INR) 1.5 ULN, activated partial thromboplastin time 1.5 ULN or prothrombin time 1.5 ULN;
• Patients requiring anticoagulation therapy but with a stable INR within the recommended range according to the local guideline are eligible.
5. Serum amylase or lipase ULN at screening or known medical history of serum amylase or lipase >ULN;
6. Patients with presence of second primary malignant tumors within the last 2 years, with the exception of:
- Basal cell carcinoma of the skin
- Squamous cell carcinoma of the skin
- Carcinoma in situ of the cervix
- Carcinoma in situ of the breast
7. Clinically significant history of liver disease, including cirrhosis, current alcohol abuse, or current known active infection with human immunodeficiency virus (HIV), cytomegalovirus (CMV), hepatitis B virus (HBV), or hepatitis C virus (HCV). Active infection is defined as one requiring treatment with antiviral therapy, presence of positive test results for hepatitis B (hepatitis B surface antigen and/or total hepatitis B core antibody), or CMV or HCV antibody.
- Patients who are positive for hepatitis B core antibody are eligible only if test results are also positive for hepatitis B surface antibody and polymerase chain reaction (PCR) is negative for HBV deoxyribonucleic acid (DNA). These patients will require HBV DNA PCR monitoring, as per local standards.
- Patients who are positive for CMV or HCV serology are eligible only if testing for CMV DNA or HCV RNA is negative.
8. Any anticancer therapy, including chemotherapy, hormonal therapy, biologic therapy, vaccine, or radiotherapy within 3 weeks prior to initiation of study treatment;
9. Any granulocyte colony-stimulating factor treatment/blood transfusion within 7 days before the screening hematology test;
10. Any steroid therapy or approved targeted small molecule agents for anti- neoplastic intent within 7 days or approximately 5 half-lives, whichever is longer, prior to initiation of study treatment;
11. PrioruseofanydrugthatisastronginducerofcytochromeP450(CYP)3A4 or strong inhibitor of CYP3A4 within 2 weeks prior to initiation of study treatment (3 weeks for St John’s Wort);
12. Prior autologous transplant within 6 months prior to initiation of study treatment;
13. Prior allogeneic stem cell transplant within 6 months prior to initiation of study treatment or with any evidence of active graft versus host disease or requirement for immunosuppressants within 21 days prior to initiation of study treatment;
14. Clinically significant active infection (e.g., pneumonia) or interstitial lung diseases; (including drug induced pneumonitis);
15. Major surgical procedure within 4 weeks prior to initiation of study treatment;
16. Treatment within a clinical study of an investigational agent or using an investigational device within 30 days prior to initiation of the current study treatment;
17. Adverse events from prior anti-neoplastic therapy that have not resolved to Grade 1, except for alopecia;
18. Pregnant (positive serum beta human chorionic gonadotropin [β-HCG] or urine test) or lactating women;
19. New York Heart Association (NYHA) Class II or greater congestive heart failure;
20. Congenital long QT syndrome or QTc >470 msec;
21. Currently use medication known to cause QT prolongation or torsades de pointes (see full list at http:// www.crediblemeds.org);
22. History of myocardial in farction or unstable angina with in 6 months prior to initiation of study treatment;
23. History of stroke or transient ischemic attack within 6 months prior to initiation of study treatment;
24. Inability to take oral medication, prior surgical procedures affecting absorption, or active peptic ulcer disease;
25. History of inflammatory bowel disease (e.g., Crohn’s disease or ulcerative colitis);
26. Patients with ongoing chronic gastrointestinal diseases;
27. Legally protected adults;
28. Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding that, in the investigator’s opinion, gives reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or renders the patient at high risk from treatment complications.
This is a phase 1, open-label, multicenter study of HMPL-689 administered orally to patients with relapsed, refractory, or resistant lymphoma. This study will consist of a dose escalation stage (Stage 1) and a dose expansion stage (Stage 2). Both Stage 1 and Stage 2 include the following periods: screening period, treatment period, safety follow-up period, and extended progression-free survival (PFS) follow-up period.