A phase II study of linperlisib (YY-20394) in patients with relapsed or refractory peripheral T/NK cell or Cutaneous T Cell lymphoma

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Shanghai Yingli Pharmaceutical Co. Ltd., Shanghai Yingli Pharmaceutical Co. Ltd.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

17 Jan 2023 → 17 Jul 2024

Decision date (initial)

2022-11-25

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Safety, Efficacy

To evaluate the overall response rate (ORR) as assessed by an Independent Radiology Review Committee (IRRC) in patients with R/R PTCL or R/R CTCL treated with linperlisib

Secondary objectives 5

1. To evaluate duration of response (DOR) in patients with R/R PTCL or R/R CTCL treated with linperlisib
2. To evaluate progression-free survival (PFS), Overall survival (OS) and Time to response (TTR) in patients with R/R PTCL or R/R CTCL treated with linperlisib
3. To evaluate the safety and tolerability of linperlisib monotherapy.
4. To evaluate the pharmacokinetic (PK) of linperlisib monotherapy.
5. Exploratory: to evaluate tumor biopsy tissue and blood for gene mutations and biomarkers correlating with response to linperlisib monotherapy

Conditions and MedDRA coding

Relapsed or Refractory Peripheral T/NK Cell or Cutaneous T Cell Lymphoma

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 17

1. Adult patient ≥18 years of age at the time of signing the informed consent.
2. Diagnosis of one of the following histologic subtypes of PTCL, pathologically confirmed, as defined by the WHO 2017 classification system: Peripheral T-cell lymphoma-not otherwise specified (PTCL-NOS) Angioimmunoblastic T-cell lymphomas (AITL) Anaplastic large cell lymphoma (ALCL). ALK positive or ALK negative Natural-killer/T-cell lymphoma (NKTCL) Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL).
3. Has received and failed at least one line of systemic therapy for PTCL.
4. Diagnosis of one of the following histologic subtypes of CTCL, pathologically confirmed, and stage ≥ Ib as defined by Olsen 2007: a) Mycosis fungoides (MF) b) Sézary syndrome (SS)
5. Has received and failed at least one line of systemic therapy for stage ≥ IIb CTCL, and at least two lines of systemic therapy for stages Ib and II CTCL.
6. Not a candidate for autologous or allogeneic transplantation.
7. For patients with CD30+ PTCL, progressed on or are ineligible or intolerant to brentuximab vedotin, or progressed on or are ineligible or intolerant to regional standard of care if brentuximab vedotin not approved or not available.
8. Agree to provide archival tumor tissue samples or undergo pretreatment fresh tissue biopsy.
9. Has radiographically measurable disease of PTCL as per Lugano Criteria with at least one measurable disease lesion > 1.5 cm in at least one dimension (which has not been previous radiated) by 18FDG-PET-CT, MRI, or diagnostic CT within 28 days prior to start of study treatment.
10. Has measurable disease of CTCL defined by at least one of the following, within 28 days prior to start of study treatment: Revised International Working Group (Oslen, 2011) Classification for systemic lymphoma or Atypical and/or malignant lymphocytes quantifiable by flow cytometry or morphology in blood mSWAT (Modified Severity Weighted Assessment Tool) >0
11. Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
12. Has adequate organ function as defined below: System Laboratory Value Haematological Absolute neutrophil count ≥1.0×109/L Note: No growth factor supports within 14 days of first dose Platelet count ≥75×109/L Note: ≥50 × 109/L for patients with bone marrow infiltration No blood product transfusion is allowed within 14 days of first dose Haemoglobin ≥8.0 g/L Note: criteria must be met without erythropoietin dependency and no blood product transfusion is allowed within 14 days of first dose Hepatic Total bilirubin ≤1.5×ULN Note: Patients with Gilbert’s Syndrome or other benign congenital hyperbilirubinemia may be eligible at the Investigator’s discretion in consultation with the Medical Monitor, if ≤ 3 × ULN Alanine aminotransferase ≤2.5×ULN Note: ≤ 5 × ULN if there is liver involvement by lymphoma Aspartate aminotransferase ≤2.5×ULN Note: ≤ 5 × ULN if there is liver involvement by lymphoma Renal CrCl calculated by Cockcroft-Gault formula CrCl ≥50 mL/min Coagulation INR < 1.5 without anti-coagulation therapy Activated partial thromboplastin time aPTT ≤1.5 ULN Cardiac Left ventricular ejection fraction LVEF ≥ 50% by an echocardiogram (ECHO) or multigated acquisition scan (MUGA). QTcF <470 ms Abbreviations: CrCl=creatinine clearance; RBC=red blood cell; QTcF=QT interval corrected using Fridericia’s formula; ULN=upper limit of normal.
13. CTCL patients who are on low or intermediate potency topical corticosteroids or low dose (≤ 10mg prednisone or equivalent) systemic steroids may participate and continue the steroids use, if they are on a stable dose for at least 4 weeks before the start of study treatment. Local injections of corticosteroids are acceptable; all corticosteroids will be reported as concomitant medications.
14. Male patients are eligible to participate if they agree to use a highly effective contraception as detailed in Appendix 4 of this protocol during the treatment period and for at least 3 months after the last dose of study treatment and refrain from donating sperm during this period
15. Female patients are eligible to participate if they are not pregnant (see Appendix 4), not breastfeeding, and at least one of the following conditions applies: Not a woman of childbearing potential (WOCBP) as defined in Appendix 4. OR A WOCBP who agrees to use a contraceptive method that is highly effective (with a failure rate of <1% per year), or be abstinent from heterosexual intercourse as their preferred method and usual lifestyle as described in Appendix 4, beginning the time of informed consent, during the treatment period and for at least 3 months after the last dose of study treatment. A WOCBP must have a negative serum pregnancy within 72 hours of the first dose of study treatment.
16. Patient is capable of giving signed informed consent.
17. Must be willing and able to adhere to the study and lifestyle restrictions as judged by the investigator.

Exclusion criteria 33

1. Patients with peripheral T-cell lymphoma having known central nervous system (CNS) invasion (either CNS lymphoma or leptomeningeal lymphoma).
2. Has clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke (<6 months prior to enrollment), myocardial infarction (<6 months prior to enrollment), unstable angina, congestive heart failure (New York Heart Association Classification Class ≥II), or serious cardiac arrhythmia requiring medication, any other cardiac disorder not suitable for participation in this study based on the judgment of the investigator. Note: During the treatment period, patients should not take medication that may prolong the QT (such as antiarrhythmic drugs).
3. Presence of multiple factors affecting drug administration and absorption such as inability to swallow, diarrhea of CTCAE Grade >1, and ileus.
4. Has a history of or concurrent interstitial lung disease of any severity and/or severely impaired lung function.
5. Prior history of drug-induced colitis or drug-induced pneumonitis.
6. Has active viral, bacterial, fungal infection or other serious infection requiring systemic treatment within 14 days before the first dose of study treatment. Routine antimicrobial prophylaxis is permitted.
7. Medical history of active bleeding within 2 months prior to study entry, or susceptible to bleeding by the judgement of investigator
8. Use of therapeutic doses of warfarin sodium (Coumadin), or any other coumarin-derivative anticoagulants. The administration of low-molecular weight heparin is allowed.
9. Unresolved toxicities from prior anti-tumor therapy, defined as not having resolved to CTCAE version 5.0 grade 0 or 1 with the exception of alopecia and peripheral neuropathy.
10. Medical history of other primary malignant tumors in the past 3 years, or any evidence of residual disease from a previously diagnosed malignancy. Note: Exceptions are patients with basal cell carcinoma of the skin, squamous cell carcinoma of the skin or carcinoma in situ (e.g., breast, cervical cancer in situ, superficial bladder tumors [Ta and Tis; carcinoma in situ]) who have undergone curative therapy with no evidence of recurrence, localized prostate cancer previously fully resected undergoing surveillance or other adequately treated Stage 1 cancer currently in complete remission.
11. Has received prior treatment with linperlisib (YY-20394), or other PIK3-δ inhibitors. Patients who have received prior treatment with other PIK3-δ inhibitors or PIK3-δ, -γ dual inhibitors, but were intolerant to them, maybe included, only at investigators’ discretion and approved by the Sponsor.
12. Has received prior treatment with rituximab or other unconjugated antibody treatment within 28 days (21 days if clear evidence of progressive disease or immediate treatment is mandated) prior to the first dose of study treatment.
13. Has received radioimmunoconjugates or toxin conjugates within 12 weeks before the first dose of study treatment.
14. Has had received prior systemic cytotoxic anticancer therapy, or definitive radiotherapy within 28 days (14 days for palliative radiation) prior to the first dose of study treatment.
15. Has received prior targeted small molecule therapy, or systemic retinoids, interferons, vorinostat, romidepsin and denileukin diftitox within 14 days or 5 half-lives whichever is longer prior to the first dose of study treatment.
16. Has received topical retinoids, nitrogen mustard, imiquimod within 1 week prior to the first dose of study treatment.
17. Has undergone major surgery (excluding lymph node biopsy) or significant trauma ≤4 weeks before the first dose of study treatment. Note: patients must have recovered adequately from surgery prior to starting study treatment.
18. Has had autologous stem cell transplant within 3 months prior to first dose of study treatment.
19. Has allogeneic transplant or solid organ transplant within 6 months prior to the first dose of study drug. CTCL patients with history of allogeneic transplant will be excluded.
20. Has graft versus host disease (GvHD) or who still require immunosuppression.
21. Use of medications or foods that are strong cytochrome CYP3A inhibitors, strong CYP3A inducers within 14 days prior to first dose of study treatment or 5 half-lives of the given drug, whichever is longer.
22. Use of any drug that may result in QT prolongation (e.g., antiarrhythmic agents) cannot be interrupted during the study.
23. Has medical conditions requiring the use of immunosuppressive medications (in dosing exceeding 20 mg prednisone or equivalent) within 14 days of the first dose of study treatment.
24. Has received a live vaccination within 30 days before the first dose of study treatment or is scheduled to be administered during the study period. Examples of live vaccines include but are not limited to the following: measles, mumps, rubella, varicella/zoster, yellow fever, Bacille Calmette-Guérin (BCG) and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed.
25. Human immunodeficiency virus (HIV) infection with a current or a known history of acquired immunodeficiency syndrome (AIDS)-defining illness or HIV infection with a CD4+ T cell count <350 cells/µL and an HIV viral load more than 400 copies/µL.
26. Patients with active viral (any etiology) hepatitis are excluded.  Patients with a history of hepatitis C virus (HCV) infection who have completed curative antiviral treatment and have a viral load below the limit of quantification may be eligible and should be discussed with the Medical Monitor.
27. Patients with active Epstein-Barr virus (EBV) infection unrelated to underlying lymphoma with positive PCR and clinical manifestation consistent with active EBV infection at screening will not be enrolled in the study.
28. Patients who have a positive PCR test for CMV and clinical manifestation consistent with active CMV infection at screening will not be enrolled in the study.
29. Unable or unwilling to receive prophylaxis against pneumocystis, herpes simplex virus, or herpes zoster.
30. Has a history or current evidence of any condition, laboratory abnormality or other circumstances that might confound the results of the study or interfere with participation for the full duration of the study, such that it is not in the best interests of the patient to take part in the study.
31. Has a history of hypersensitivity to linperlisib (YY-20394) and/or any excipients.
32. Has a known psychiatric disorder that would interfere with compliance with the requirements of the study.
33. Is a regular user of illicit or recreational drugs or has a recent history (within the last year) of drug or alcohol abuse or dependence.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Overall response rate (ORR = CR + PR) for PTCL, from start of treatment to first documented response, measured by Lugano 2014 Response Criteria for NHL (Cheson 2014) Overall response rate (ORR = CR + PR) for CTCL, from start of treatment to first documented response, based on Olsen Global Response Score (Olsen 2011)

Secondary endpoints 5

1. DOR, defined as time from first documentation of a response (PR or CR) to the first documented disease progression or death due to any cause, whichever occurs first, for those patients with a PR or CR.
2. PFS, defined as the time from start of treatment to first documented disease progression or death due to any cause, whichever occurs first. Overall survival (OS) Time to response (TTR)
3. Incidence and severity of Adverse events (AEs) using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0 Discontinuation of study treatment due to an AE
4. PK parameters include: AUClast, AUCinf, Cmin, Cmax, T1/2, and Tmax.
5. Exploratory: to investigate correlations between protein biomarkers, immune cells, and gene mutations in PTCL or CTCL tumors and blood with response and survival

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Shanghai Yingli Pharmaceutical Co. Ltd.

Sponsor organisation

Shanghai Yingli Pharmaceutical Co. Ltd.

Address

Building 4 Room 311, No 576 Li Bing Road, Testing Zone No 576 Li Bing Road Testing Zone

City

Shanghai

Postcode

201203

Country

China

Scientific contact point

Organisation

Shanghai Yingli Pharmaceutical Co. Ltd.

Contact name

Meiyue Hong

Public contact point

Organisation

Shanghai Yingli Pharmaceutical Co. Ltd.

Contact name

Meiyue Hong

Third parties 4

Shanghai Yingli Pharmaceutical Co. Ltd.

Sponsor organisation

Shanghai Yingli Pharmaceutical Co. Ltd.

Address

Building 4 Room 311, No 576 Li Bing Road, Testing Zone No 576 Li Bing Road Testing Zone

City

Shanghai

Postcode

201203

Country

China

Scientific contact point

Organisation

Shanghai Yingli Pharmaceutical Co. Ltd.

Contact name

Meiyue Hong

Public contact point

Organisation

Shanghai Yingli Pharmaceutical Co. Ltd.

Contact name

Meiyue Hong

Third parties 4

Locations

1 EU/EEA country · 3 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Application history

3 submissions — initial application plus substantial / non-substantial modifications