Agnostic Therapy in Rare Solid Tumors

The ANTARES study is a phase II basket trial designed to evaluate the tissue-agnostic efficacy of the monoclonal anti-PD1 antibody, nivolumab, in patients with advanced or metastatic rare tumors.

The study aims to treat rare malignancies with PD-L1 expression (CPS ≥ 10), regardless of the tumor's tissue type or location. Patients who have not responded to standard treatments will be included, and treatment will last for up to 12 months. The study will assess objective response, progression-free survival, and biomarkers such as PD-L1, ctDNA, and microvesicles, in a multicenter collaborative effort to provide innovative therapeutic options for this underrepresented population

The ANTARES study is a phase II "basket" trial designed to evaluate the tissue-agnostic efficacy of the monoclonal anti-PD1 antibody, nivolumab, in patients with advanced or metastatic rare tumors. A "basket" trial is an innovative type of clinical trial where patients with different types of cancers, but sharing a common molecular feature (in this case, PD-L1 expression), are treated with the same therapy, regardless of the tumor's site of origin. This approach allows for the evaluation of treatments targeting specific molecular characteristics, independent of the primary cancer type.

Rare tumors, as defined by the World Health Organization (WHO), have an incidence of fewer than six cases per 100,000 people per year. Although each rare cancer type is individually uncommon, collectively they account for 25-30% of all malignancies and are often underrepresented in clinical trials due to recruitment challenges and limited funding. As a result, patients with rare cancers generally have a poorer prognosis compared to those with more common tumors.

In this study, patients with advanced or refractory rare malignancies expressing PD-L1, with a combined positive score (CPS) of ≥10, will be treated with nivolumab. Treatment will be administered until disease progression or for a maximum duration of 12 months, aiming to assess the efficacy and safety of this tissue-agnostic immunotherapy approach. Efficacy will be measured according to RECIST v1.1 criteria, with objective response as the primary endpoint. Additionally, the study will assess response biomarkers, including PD-L1, circulating tumor DNA (ctDNA), and microvesicles, to better understand the correlation between biomarker expression and clinical outcomes.

This multicenter trial, with an estimated duration of four years, will be conducted at Institute of Cancer of the State of São Paulo (ICESP) and other partner institutions. The study aims to overcome existing barriers in rare cancer treatment by offering an innovative approach that explores the potential of personalized therapies based on molecular characteristics, rather than the tumor's primary site

Eligibility Criteria:
Inclusion Criteria

1. Age 18 years or older.
2. Patients with immunohistochemistry for PD-L1 with a combined positive score (CPS) of 10 or higher.
3. Patients with progression or intolerance to already approved and accessible treatments for the specific neoplasm and population.
4. Documented disease progression radiologically after the last routine treatment.
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
6. Measurable lesion per RECIST v1.1. Lesions previously treated with radiotherapy can only be used as target lesions if they are confirmed to be progressing by imaging before enrollment.
7. Male participants must meet at least one of the following conditions:

   1. Considered infertile;
   2. No fertile partner;
   3. Has a fertile partner who agrees to follow contraceptive guidance throughout the study period and for at least 6 months after the last dose of Nivolumab;

      and
   4. Agrees to abstain from sperm donation throughout the study period and for at least 6 months after the last dose of Nivolumab.
8. Female participants must meet at least one of the following conditions:

   1. Considered infertile;
   2. Agrees to follow contraceptive guidance throughout the study period and for at least 6 months after the last dose of Nivolumab;
9. Estimated life expectancy greater than 12 weeks, as determined by the investigator or delegated sub-investigator.
10. Preserved organ functions defined by:

    * Absolute neutrophil count ≥ 1,000;
    * Hemoglobin ≥ 8.0 g/dL (patients may receive transfusions to reach this level);
    * Platelet count ≥ 100,000;
    * Total bilirubin ≤ 1.5 × Upper Limit of Normal (ULN), or ≤ 3.0 × ULN for patients with Gilbert's syndrome;
    * Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) ≤ 2.5 × ULN (≤ 5 × ULN in the presence of liver metastases);
    * Creatinine clearance \> 30 mL/min (estimated by Cockcroft-Gault).
11. Diagnosis of rare cancer (List I) confirmed by histopathological examination, with the possibility of including other types of rare tumors (incidence of less than 6 in every 100,000) after careful evaluation and approval by the study board.

    * List I:

      * Urachal adenocarcinoma
      * Parathyroid carcinoma
      * Nasopharyngeal epithelial tumors
      * Fibrolamellar carcinoma of any primary site
      * Angiosarcoma of any primary site
      * Secretory breast carcinoma
      * Anal cancer
      * Metaplastic breast carcinoma
      * Chromophobe renal carcinoma, Microphthalmia-associated Transcription Factor (MiT) family translocation renal carcinoma; renal carcinoma with Fumarate Hydratase (FH) or Succinate Dehydrogenase (SDH) deficiency
      * Carcinosarcoma of any primary site
      * Small intestine cancer
      * Cholangiocarcinoma
      * Sertoli-Leydig cell tumors
      * Cervical cancer of non-epidermoid histology
      * Tracheal epithelial tumors
      * Non-cystadenoma salivary gland tumors
      * Mesothelioma of any site
      * Neuroblastoma
      * Adrenal cancer
      * Penile cancer
      * Apocrine carcinoma
      * Fibrosarcoma of any primary site
      * Cancer of unknown primary site
      * Hemangioblastoma of any primary site
      * Thyroid cancer
      * Hepatoblastoma
      * Fallopian tube cancer
      * Leiomyosarcoma of any primary site
      * Vaginal cancer
      * Neurofibrosarcoma of any primary site
      * Gallbladder cancer
      * Osteosarcoma of any primary site
      * Bile duct cancer
      * Clear cell endometrial carcinoma
      * Yolk sac tumor of any primary site
      * Non-epidermoid bladder cancer
      * Vulvar cancer
      * Kaposi's sarcoma
      * Epithelial ovarian cancer
      * Soft tissue sarcoma
      * Urethral cancer
      * Granulosa cell tumor of any primary site
      * Cystadenoma carcinoma
      * Primitive neuroectodermal tumor of any primary site
      * Pure or mixed neuroendocrine tumors with neuroendocrine component
      * Trophoblastic tumor

Exclusion Criteria

1. Previous treatment lines with immunotherapy (immune checkpoint inhibitors).
2. Pregnant or breastfeeding individuals.
3. Limiting comorbidity, in the opinion of the investigator.
4. Active infection.
5. Major surgery within the last 4 weeks.
6. Functional class II or greater heart failure.
7. Myocardial infarction or stroke within the last 6 months.
8. History of pulmonary fibrosis or pneumonitis.
9. Autoimmune diseases, except for patients with vitiligo and/or controlled thyroid/hypothyroidism without the use of immunosuppressors.
10. Second invasive primary tumor diagnosed in the last 3 years and/or with active disease, except for localized skin tumors (non-melanoma) that have been treated with curative intent.
11. Patients with prolonged QT interval.
12. Uncontrolled Central Nervous System (CNS) metastases. Patients who have previously received local treatment, such as radiotherapy, will be eligible if clinical and radiological stability is demonstrated in the 2 weeks prior to the start of treatment. Patients must not be using corticosteroids for managing CNS disease.
13. Presence of meningeal carcinomatosis.
14. Worsening renal and liver function in the 14 days prior to enrollment.
15. History of solid organ transplantation with or without immunosuppression.
16. Patients with untreated acquired immunodeficiency. Immunocompromised patients may be included as long as they do not have active opportunistic disease and/or active infection, after thorough clinical evaluation by the investigator or sub-investigator. HIV-positive patients must have documented undetectable viral load prior to inclusion.
17. Chronic use of corticosteroids at doses greater than 10 mg/day of prednisone or equivalent. Patients with adrenal insufficiency of non-autoimmune etiology (e.g., previous bilateral adrenalectomy) may be included if they are clinically compensated with 10 mg/day of prednisone or equivalent or less.