Clinical Research
assignment
Not Yet Recruiting

Phase 1/2 Study to Evaluate the Safety, Tolerability, and Efficacy of PTT-4256 Monotherapy or in Combination with Nivolumab in Patients with Solid Tumours

Trial ID
2025-522944-41-00
Protocol
PTT-4256-01
Sponsor
Pathios Therapeutics Limited

Trial statistics

science
6
test molecules
location_city
9
research sites
public
2
countries
medical_information
2
diseases
person_search
10
investigators
handshake
11
vendors

Diseases & Conditions

Squamous cell carcinoma of head and neckRenal cell carcinoma

Objectives

The primary objective of this study is to evaluate the safety and tolerability of PTT-4256 in patients with solid tumours, administered either as a monotherapy or in combination with an approved PD-1/PD-L1 inhibitor. Secondary objectives include:

  • Confirmation of the safety of the recommended phase 2 dose (RP2D) or optimal biological dose (OBD) of PTT-4256 as a monotherapy and/or in combination with an approved PD-1/PD-L1 inhibitor.
  • Assessment of the preliminary efficacy of PTT-4256 in specific tumour types through monotherapy or combination therapy within expansion cohorts.
  • Characterisation of the plasma pharmacokinetics of PTT-4256 in expansion cohorts.
  • Evaluation of pharmacodynamics.

Participants

This study includes 55 participants diagnosed with various solid tumours. The study population comprises adults, including both male and female individuals. Eligible participants must have a histologically confirmed diagnosis of unresectable locally advanced or metastatic clear cell renal cell carcinoma, papillary renal cell carcinoma, or head and neck squamous cell carcinoma. Participants are required to have measurable disease according to RECIST v1.1 and an Eastern Cooperative Oncology Group performance status of 0 to 1. Selection is based on the requirement for systemic treatment following progression or intolerance to standard-of-care therapies, including PD-1/PD-L1 inhibitors and VEGF tyrosine kinase inhibitors. Additionally, participants must possess adequate haematological, hepatic, and renal function, and an estimated life expectancy of at least 3 months. Availability of a formalin-fixed paraffin-embedded tumour tissue sample from a biopsy is mandatory for all subjects.

Plans and Procedures

This Phase 1/2, open-label, modular clinical trial is designed to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of PTT-4256 in patients with solid tumours. The study investigates the administration of PTT-4256 as a monotherapy or in combination with a PD-1/PD-L1 inhibitor, such as nivolumab. The research methodology includes a screening visit to assess eligibility based on histological diagnosis, measurable disease per RECIST v1.1, and specific hematological and organ function requirements. The trial is expected to occur between February 2026 and February 2029. Participants will undergo various study visits to monitor adverse events and assess tumour response via cross-sectional imaging. Overall survival will be monitored through study participation and subsequent telephone follow-ups every three months. Early termination from the study may occur based on investigator assessment of clinical status or safety concerns.

Treatment

PTT-4256 is administered as an oral tablet. This substance is investigated for use as a monotherapy or in combination with a PD-1/PD-L1 inhibitor.

Nivolumab is provided as a solution for infusion in a 10 mg/mL concentrate. This medication is administered via infusion.

Efficacy

The assessment of preliminary efficacy in patients with solid tumours involves several clinical endpoints. The objective response rate (ORR), disease control rate (DCR), duration of response (DoR), and progression-free survival (PFS) will be evaluated through cross-sectional imaging. These assessments will be performed according to RECIST v1.1 and/or iRECIST criteria based on investigator assessment.

Additional efficacy evaluation includes the measurement of overall survival (OS) during the study period and through telephone follow-ups conducted every 3 months. Furthermore, plasma pharmacokinetics (PK) parameters, such as Cmin, Cmin_ss, and accumulation ratio (RA Cmin), will be analyzed.

Inclusion and Exclusion Criteria

check_circle

Inclusion Criteria

  • ≥ 18 years of age at the time of consent.
  • Participant has given written informed consent to participate in the study and is able and willing to adhere to the study protocol.
  • Participant has measurable disease per RECIST v1.1.
  • Participant has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
  • Participant has an estimated life expectancy of at least 3 months in the opinion of the Investigator.
  • Adequate haematological (blood or platelet transfusion not allowed within 7 days prior to Screening), liver, and renal function defined below (repeat measurement of borderline values permitted): • Haemoglobin ≥ 8.5 g/dL, • Absolute neutrophil count (ANC) ≥ 1.5 × 109/L, • Platelet count ≥ 90 x 109/L, • Total bilirubin ≤ 1.5 institutional upper limit of normal (ULN), (or where ≤ 2 × ULN with known hepatobiliary metastases or Gilbert’s syndrome), • Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 2.5 × ULN (or ≤ 5 × ULN if liver metastases are present), • Estimated glomerular filtration rate (eGFR) > 30 mL/min/1.73 m2 (calculated using Cockcroft-Gault).
  • Females: a. must not be pregnant or lactating, and b. must use acceptable, highly effective contraception from Screening until:  90 days after last IMP administration (Module A and Module B1) or  5 months after last IMP administration (Module B2 and Module B3). Effective forms of contraception are defined in Section 7.3.2. c. females with same-sex partners (abstinence from penile-vaginal intercourse) or who are abstinent from heterosexual intercourse are not required to use contraception when this is their preferred and usual lifestyle, and d. women of childbearing potential (WOCBP) must have a negative pregnancy test at Screening and Day 1 and be willing to have additional pregnancy tests as required throughout the study. WOCBP must not donate ova from signing informed consent until: - at least 90 days after the last IMP administration (Module A and Module B1) or - at least 5 months after the last IMP administration (Module B2 and Module B3). WOCBP are defined in Section 7.3.2, or e. women of non-childbearing potential (WONCBP) must be surgically sterile (hysterectomy, bilateral oophorectomy, or bilateral salpingectomy) or postmenopausal (no menses for ≥ 12 months; or ≥ 60 years of age at the time of consent (postmenopausal status is to be confirmed through testing of follicle-stimulating hormone [FSH] levels ≥ 40 IU/L [except for participants on hormone replacement therapy] at Screening for amenorrhoeic female participants).
  • Males: a. must be surgically sterile (> 6 months since vasectomy with confirmation of no viable sperm), or b. males with same-sex partners (abstinence from penile-vaginal intercourse) or who are abstinent from heterosexual intercourse are not required to use contraception when this is their preferred and usual lifestyle, or c. if engaged in sexual relations (intercourse) with a WOCBP, either his partner must be surgically sterile (eg, hysterectomy, bilateral salpingectomy, bilateral oophorectomy), or a barrier contraceptive method (condom) plus a highly effective contraceptive method (see Section 7.3.2) must be used from Screening until at least 90 days after the last IMP administration, and d. Males must not donate sperm from the first dose of IMP until at least 90 days after the last dose of IMP administration.
  • Additional Module B1 Specific Inclusion Criteria - Participant has histologically confirmed diagnosis of unresectable locally advanced or metastatic RCC including ccRCC or pRCC.
  • Additional Module B1 Specific Inclusion Criteria - A formalin fixed, paraffin-embedded (FFPE) tumour tissue block or unstained slides of tumour sample (archival or recent) must be available. Sample should be from a tumour biopsy (eg, excisional, incisional, core needle), as cytological samples (eg, fine needle aspiration) are insufficient.
  • Additional Module B1 Specific Inclusion Criteria - Participant requires systemic treatment for their cancer, and either a. be refractory to, b. have progressed on, c. be intolerant to, or d. be not otherwise a candidate, in the opinion of the Investigator, for any of the currently available standard treatments including, at least, a PD-1/PD-L1 inhibitor and VEGF TKI.
  • Additional Module B2 Specific Inclusion Criteria - Participant has histologically confirmed diagnosis of unresectable locally advanced or metastatic ccRCC.
  • Additional Module B2 Specific Inclusion Criteria - A FFPE tumour tissue block or unstained slides of tumour sample (archival or recent) must be available. Sample should be from a tumour biopsy (eg, excisional, incisional, core needle), as cytological samples (eg, fine needle aspiration) are insufficient.
  • Additional Module B2 Specific Inclusion Criteria -Participant requires systemic treatment for their cancer, and either be refractory to or have progressed on both a VEGF and a PD-1/PD-L1 inhibitor therapy (administered as combination therapy or as a part of separate prior lines of treatment) if not otherwise contraindicated. Radiologically confirmed disease progression must be demonstrated for the most recently administered regimen, prior to study participation.
  • Additional Module B2 Specific Inclusion Criteria - Participants should not have an intolerable toxicity to prior anti-PD-1/PD-L1 therapy and, in the opinion of the Investigator, are suitable to receive further checkpoint blockade with nivolumab.
  • Additional Module B2 Specific Inclusion Criteria - Participants must be eligible to receive nivolumab at the approved dose and schedule according to the current Summary of Product Characteristics (SmPC) (eg, OPDIVO®).
  • Additional Module B3 Specific Inclusion Criteria - Participant has histologically confirmed diagnosis of unresectable locally advanced or recurrent or metastatic HNSCC of oral cavity, pharynx, larynx which is not amenable to local therapy with curative intent (surgery or radiation therapy with or without chemotherapy). Recurrent or metastatic carcinoma of the nasopharynx and salivary gland or non-squamous histologies (eg, mucosal melanoma) are not allowed.
  • Additional Module B3 Specific Inclusion Criteria - Participant requires systemic treatment for their cancer, and must have progressed on standard-of-care systemic therapy, including both a PD-1/PD-L1 inhibitor (monotherapy or combination) and a chemotherapy regimen; such progression may have occurred in the metastatic / recurrent setting or within 6 months following peri-operative treatment.
  • Additional Module B3 Specific Inclusion Criteria - A FFPE tumour tissue block or unstained slides of tumour sample (archival or recent) must be available. Sample should be from a tumour biopsy (eg, excisional, incisional, core needle), as cytological samples (eg, fine needle aspiration) are insufficient.
  • Additional Module B3 Specific Inclusion Criteria - Documentation of p16-positive or p16-negative disease to determine human papillomavirus (HPV) status of tumour for SCC of the oropharynx.
  • Additional Module B3 Specific Inclusion Criteria - Participants should have not an intolerable toxicity to prior anti-PD-1/PD-L1 therapy and, in the opinion of the Investigator, are suitable to receive further checkpoint blockade using Nivolumab.
  • Additional Module B3 Specific Inclusion Criteria - Participants must be eligible to receive nivolumab at the approved dose and schedule according to the current SmPC (eg, OPDIVO®).
cancel

Exclusion Criteria

  • Inability or unwillingness to adhere to the study protocol, including study procedures and oral intake of the IMP.
  • Patients with known leptomeningeal disease or untreated, symptomatic, or progressing central nervous system (CNS) metastases. Patients with treated brain metastases will be eligible if free of progression for at least 4 weeks post-CNS therapy (eg, surgery, radiotherapy), confirmed by brain MRI at Screening, and are neurologically stable (no CNS symptoms).
  • Unresolved or unstable serious toxic side effects of prior anti-cancer therapy or radiotherapy, ie, ≥ Grade 2 per CTCAE v5.0 except fatigue, alopecia, infertility, or those relating to palliative radiotherapy within 6 weeks prior to first IMP administration. Participants with residual AEs > Grade 1 considered not clinically significant may be considered eligible on a case-by-case basis, in discussion with the Sponsor.
  • Concurrent active or previous history of other malignancy within the past 2 years before first IMP administration except: a. Malignancy (other than in situ) treated with curative intent and with no known active disease present for ≥ 2 years before first IMP administration and felt to be at low risk of recurrence by the Investigator; b. Adequately treated non-melanoma skin cancer or lentigo malignant with no evidence of disease; c. Adequately treated in situ cancer without evidence of disease.
  • Received anti-cancer therapy (including chemotherapy, immunotherapy, radiation therapy, biologic therapy, or any investigational therapy) within 28 days or 5 half-lives of the therapeutic agent, whichever is shorter, prior to the first IMP administration. Exceptions include:  Patients who received palliative radiotherapy given within 28 days prior to the first IMP administration may be considered eligible on a case-by-case basis, in discussion with the Sponsor.  Ongoing concomitant androgen deprivation therapy with GnRH agonist or GnRH antagonist for castration-resistant prostate cancer is permitted.
  • Uncontrolled symptomatic malignant effusion(s) or those requiring recurrent drainage, in the opinion of the Investigator.
  • Participants with clinically significant active autoimmune or chronic inflammatory disease that is not well controlled with standard therapy, in the opinion of the Investigator.
  • Grade 3 or higher immunotherapy-induced autoimmune hepatitis.
  • Participants with: a. symptomatic colitis of any grade as per CTCAE v5.0 and any non-infective aetiology within 4 weeks before first dosing. For any episodes of infective colitis, these should have resolved and patients should have completed antimicrobial treatment, if required, at least 1 week prior to IMP administration. b. a history of autoimmune colitis or inflammatory bowel disease, unless the condition has been resolved for > 2 years and requires no immunosuppressive therapy during this period, and/or, c. a history of drug-induced colitis of ≥ Grade 3 per CTCAE v5.0.
  • History of primary immunodeficiency, bone marrow transplantation or solid organ transplantation.
  • Use of systemic immunosuppressive medication (including > 10 mg prednisolone per day or equivalent) within 14 days prior to the first IMP administration. Note that use of immunosuppressive medications as prophylaxis in participants with contrast allergies is acceptable. Adrenal replacement corticosteroid doses > 10 mg daily prednisone equivalent are permitted, as are topical, inhaled, intra-articular or intra-nasal corticosteroids.
  • Participants with active Hepatitis B virus (HBV) hepatitis infection (defined as having a positive hepatitis B surface antigen [HBsAg] test at Screening) or Hepatitis C virus (HCV) hepatitis. Participants with resolved past HBV infection (defined as having a negative HBsAg test and a positive antibody to hepatitis B core antigen [anti-HBc] antibody test) are eligible. Participants positive for HCV antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA.
  • Participants with active HIV infection or known history of HIV infection. Participants with HIV are excluded unless CD4+ T-cell count is ≥ 350 /mm3, HIV viral load is undetectable, and the participant is on stable ART.
  • Active infection requiring systemic antibacterial, antiviral or anti-fungal therapy for ≤ 7 days of first IMP administration. Note that participants on antibacterial, anti-fungal or antiviral prophylaxis are eligible.
  • Uncontrolled or recent history of clinically significant cardiovascular disease: Symptomatic heart failure (New York Heart Association classes II-IV), unstable angina, myocardial infarction, serious/uncontrolled/unstable cardiac arrhythmia, cerebral vascular accident, coronary/peripheral artery bypass graft surgery, transient ischaemic attack, or pulmonary embolism within 4 months prior to first IMP administration. Note that participants with small pulmonary emboli not thought to put them at higher risk may be considered eligible on a case-by-case basis, in discussion with the Sponsor.
  • Confirmed Baseline QTcF > 450 msec for males and > 470 msec for females (triplicate ECG) or history of torsades de pointes or history of congenital long QT syndrome. Note that participants with an apparent prolonged QT due to bundle branch block may be considered eligible on a case-by-case basis, in discussion with the MM.
  • History of clinically significant interstitial lung disease, or active non-infectious pneumonitis, or which may interfere with the detection or management of suspected drug-related pulmonary toxicity.
  • Has had or is scheduled to have major surgery < 28 days prior to the first IMP administration. Elective surgical procedures not considered to put participants at higher risk of AEs may be allowed on a case-by-case basis, in discussion with the Sponsor.
  • Any other concurrent severe and/or uncontrolled medical, surgical or psychiatric and/or social condition which, in the view of the Investigator, could compromise the participant’s safety or ability to participate in the study and make them unsuitable for participation.
  • Use of other investigational medicinal products within 2 weeks or at least 5 half-lives (whichever is longer) before IMP administration.
  • Must not have had a live vaccine administration ≤ 28 days prior to the first dose of the IMP.
  • Participants with known active or suspected alcohol or drug abuse that may interfere with the study in the opinion of the Investigator.
  • Gastrointestinal conditions that may affect oral absorption of drugs in the opinion of the Investigator, including but not restricted to gastroparesis and short bowel syndrome.
  • Additional Module B2 and B3 Specific Exclusion Criteria - Known hypersensitivity to nivolumab (OPDIVO®) or to any of the excipients listed in the Section 6.1 (List of excipients) of the OPDIVO® SmPC.
  • Additional Module B2 and B3 Specific Exclusion Criteria - Prior immunotherapy-related toxicity that led to a. discontinuation of the immunotherapy, or b. required more than steroid therapy.
  • Additional Module B2 and B3 Specific Exclusion Criteria - Active or prior documented autoimmune or inflammatory disorders that, in the opinion of the Investigator, qualifies as a contraindication for nivolumab as per the Sections 4.3 (Contraindications) and 4.4 (Special warnings and precautions for use) of the OPDIVO® SmPC.
  • Additional Module B2 and B3 Specific Exclusion Criteria - History of pneumonitis or interstitial lung disease, unless resolved and free from requiring systemic steroids for ≥ 90 days and considered by the Investigator as not clinically significant, in line with safety considerations described in Section 4.8 (Undesirable effects) of the OPDIVO® SmPC.
  • Additional Module B2 and B3 Specific Exclusion Criteria - Concurrent use of systemic immunosuppressive agents that are contraindicated during treatment with nivolumab per Section 4.5 (Interaction with other medicinal products and other forms of interaction) of the OPDIVO® SmPC.

Trial Status by Country

Country Status Start of Recruitment Planned Patients
France FranceNot Yet Recruiting27 Feb 202625
Spain SpainNot Yet Recruiting27 Feb 202670

Sites & Investigators

Investigational Products

Details about the medicinal products being studied in this clinical trial.

Product Name Role in Trial Formulation Administration Max Daily Dose Treatment Duration EU MP Number
PTT-4256
TestTABLETORAL USE——PRD12930243
OPDIVO 10 mg/mL concentrate for solution for infusion.
TestCONCENTRATE FOR SOLUTION FOR INFUSIONINFUSION——PRD2941375
PTT-4256
TestTABLETORAL USE——PRD12930025
PTT-4256
TestTABLETORAL USE——PRD12930240
PTT-4256
TestTABLETORAL USE——PRD12930242
PTT-4256
TestTABLETORAL USE——PRD12930241

Conditions Studied in This Trial

Interventions Studied in This Trial

vaccines
Nivolumab
214 trials

Also investigated for

Non-small cell lung cancer 25Malignant melanoma 22Neoplasm 16Renal cell carcinoma 13