Phase 1/1b study to assess the drug OBT076 in patients with recurrent and/or metastatic CD205-positive solid tumors

Prior treatment

• Patient has received any cytotoxic chemotherapy within 28 days prior to Cycle 1 Day 1.
• Patient has received any other systemic anticancer therapy within 28 days or 5 half-lives of Cycle 1 Day 1, whichever is shorter (patients receiving endocrine/hormonal treatment for respective tumor types are eligible).
• Patient has a known history or current diagnosis of HIV infection, unless on triple antiviral treatment with undetectable viral load.
• Patient is a female of childbearing potential [defined as a sexually mature woman who 1) has not undergone hysterectomy (the surgical removal of the uterus) or bilateral oophorectomy (the surgical removal of both ovaries) or 2) has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time during the preceding 12 consecutive months)] and is not using any adequate form of birth control.
• Patients with grade 3 or 4 immune-related adverse reactions during any prior line of checkpoint inhibitor containing therapy. Patients with immune-related thyroiditis controlled with substitution, or prior asymptomatic lipase or amylase increases are eligible for the study.
• Patient has symptomatic visceral crisis requiring chemotherapy per Investigator judgment for non TNBC
• Patient has any other malignancy within 5 years prior to signature of ICF, with the exception of any curable cancer with a complete response of > 2 years duration that does not require or is not anticipated to require any additional therapy. Patients with adequately treated in situ carcinoma of the cervix, uterus, or non-melanomatous skin cancer (all treatment of which should have been completed 6 months prior to enrollment),) are eligible for the study.
• Patient has not recovered from the acute toxic effects (i.e., to CTCAE grade ≤ 1) of prior anticancer therapy, radiation, or major surgery/significant trauma (except alopecia or other toxicities not considered a safety risk for the patient at the Investigator’s discretion).
• Patient has had major surgery within 28 days prior to Cycle 1 Day 1 or has not recovered from major side effects. Note: Major surgery is defined as any invasive operative procedure in which a more extensive resection is performed, e.g., a body cavity is entered, organs are removed, normal anatomy is altered. Minimally invasive biopsies are not considered major surgeries.
• Patient has had radiotherapy ≤ 4 weeks or limited field radiation for palliation ≤ 2 weeks prior to starting study drug, and/or from whom ≥ 30% of the bone marrow was irradiated.
• Patient has a history of, or current symptomatic brain metastasis. Patients with asymptomatic brain metastases may participate in this study. Any prior local treatment for brain metastases must have been completed ≥ 28 days prior to the start of study treatment (including radiotherapy and/or surgery) and the patient must be receiving no or low stable dose corticosteroids. Note: For uroeoithelial cancer patients enrolling in Part E, please see specific criteria for Part E.
• Specific to part E : Patients with a condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone equivalent) within the 14 days prior to the first dose of study treatment or another immunosuppressive medication within the 30 days prior to the first dose of study treatment. Inhaled or topical steroids, and adrenal replacement steroid doses ≤10 mg daily prednisone equivalent) are permitted in the absence of active autoimmune disease.
• Specific to part E : Patients who were hospitalized during screening for infectious complications or required IV antibiotics in the 14 days prior to Cycle 1 Day 1.
• Specific to part E : Patients who received G-CSF in the 14 days prior to Cycle 1 Day 1.
• Specific to part E : Patients who had febrile neutropenia during the previous line of therapy or during the last line of therapy containing cytotoxic chemotherapy.
• Specific to part E : Patients who are primary refractory to anti-PD-(L)1 directed therapy.
• Specific to part E : Patients with NSCLC and more than 2 prior lines of systemic anti-cancer therapy in the locally-advanced/metastatic disease setting; and who received more than one prior line of cytotoxic chemotherapy in the locally-advanced/metastatic setting.
• Specific to part E : Patients with urothelial cancer who received more than 3 prior lines of systemic anticancer therapy in locally-advanced/metastatic disease setting. Prior neoadjuvant or adjuvanttherapy is not counted.
• Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine <7 days before Cycle 1 Day 1. For vaccines requiring more than 1 dose, the full series should be completed prior to Cycle 1 Day1, when feasible

Other illness

• Patient has any ongoing skin disorders not controlled by specific treatment.
• History of allogeneic organ transplant.
• Active autoimmune disease or history of autoimmune disease that required systemic treatment within 3 years of the start of study treatment (i.e. with use of disease-modifying agents or immunosuppressive drugs).
• Patients with colorectal cancer and pancreatic cancer are not eligible for the study.
• Specific to part E : Patients with urothelial cancer and any history or current CNS metastasis.
• Patient has a known or suspected hypersensitivity or other contraindication to any excipients used in the manufacture of OBT076 or balstilimab.
• Patient has any condition that confounds the ability to interpret data from the study.
• Patient has a past medical history of or ongoing clinically relevant interstitial lung disease, drug-induced pneumonitis or severe/very severe COPD.
• Patient has clinically relevant (as per discretion of the investigator) active or chronic corneal disorder or Sjogren’s syndrome.

Lab values

• Patient has significant active cardiac disease within the previous 6 months including unstable angina or angina requiring surgical or medical intervention, significant cardiac arrhythmia, or NYHA class 3 or 4 congestive heart failure, or patients with QTc interval >470ms at screening.
• Specific to part E : Patients who presented in the 14 days prior to or on Cycle 1 Day 1 with one or more of the following: - ANC of <1.5 x 109 cells/L - Platelets of <100 x 109 cells/L - Hemoglobin of <9 g/dL.
• Patient has any significant medical condition, laboratory abnormality, or psychiatric illness that would, in the Investigator’s judgment, contraindicate patient participation in the study (e.g., history of thromboembolic event, cardiac dysfunction, chronic pancreatitis, chronic active hepatitis).

Other

• Patient is unable or unwilling to take folic acid or vitamin B12 supplementation.
• Patients with extensive peritoneal involvement, i.e., peritoneal carcinomatosis, are not eligible for the study. This criterion is not applicable to patients enrolling in Part E of this study.
• Specific to part E : The presence of any contraindication to gemcitabine as per applicable Summary of Product Characteristics/label.
• Patient is lactating or breastfeeding.

• Patient is ≥ 18 years of age (at the time of signing the ICF) with non-curative recurrent and/or metastatic solid tumors who have progressed on standard treatments or for which a standard therapy is not available or is no longer effective, or who has no satisfactory treatment options.
• Patient has an ECOG performance status of 0-1.
• Patient has radiological documented measurable disease (i.e., at least 1 measurable lesion as per RECIST Version 1.1). a. For breast cancer if no measurable disease is present, then at least 1 predominantly lytic bone lesion must be present.
• Patient has adequate organ function, evidenced by the following: a. AST (SGOT), ALT (SGPT) ≤ 2.5 x ULN, or ≤ 5 x ULN range if liver metastasis present. b. Total bilirubin ≤ 1.5 x ULN. c. Estimated creatinine clearance at least 30 ml/min as per cockroft-gault or MDRD formula. d. Potassium within normal range (according to local lab), or correctable with supplements.
• Patient has adequate bone marrow function, evidenced by the following: a. ANC ≥ 2.0 x 109 cells/L. b. Platelets ≥ 100 x 109 cells/L. c. Hemoglobin ≥ 9 g/dL.
• Specific to part D : Patients with solid tumors (types defined as below for Cohort D1, D2 and D3) who have progressed on standard treatments or for which a standard therapy is not available or is no longer effective, or who has no satisfactory treatment options. Cohort D1: Patients with metastatic NSCLC who are primary (Cohort D1a) or secondary (Cohort D1b) refractory to prior anti-PD-(L)1 directed therapy. Patient with NSCLC and actionable driver mutations must have received at least one prior line of TKI in the metastatic setting. Cohort D2: Patients with metastatic cancers of breast, stomach, esophagus, gastro-esophageal junction, urothelium, cervix, endometrium, or kidney (only clear-cell) who are primary (Cohort D2a) or secondary (Cohort D2b) refractory to prior anti-PD-(L)1 directed therapy. Patients in Cohort D1 and D2 must have progressed on or after the most recent line of therapy containing anti-PD-(L)1 directed therapy (monotherapy or combination therapy). If this line was not the immediate prior line of therapy, then the patient must have received the last dose of anti-PD-(L)1 directed therapy within 24 months prior to signature of pre-screening or main screening ICF (whichever is earlier), or must have received a maximum of 2 systemic lines of therapy after the last anti-PD-(L)1 containing therapy. Cohort D3: Patients with recurrent locally advanced or metastatic adenoid cystic carcinoma, irrespective of prior treatment status with checkpoint inhibitors. Patients must have radiographically documented progression prior to enrollment into the study.
• Specific to part D : Patients with a condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone equivalent) within 14 days or another immunosuppressive medication within 30 days of the first dose of study treatment. Inhaled or topical steroids, and adrenal replacement steroid doses (≤10 mg daily prednisone equivalent), are permitted in the absence of active autoimmune disease.
• Specific to part E : Patients with stage IV NSCLC or stage III/stage IV urothelial cancer who have progressed on standard treatments or for whom a standard therapy is not available, standard therapy is no longer effective, or who have no satisfactory treatment options. Cohort E1: Patients must have histologically or cytologically confirmed Stage IV nonsmall cell lung cancer (NSCLC) and must have received exactly one prior line of systemic therapy in the advanced/metastatic setting, which must have included: An anti-PD-1 or anti-PD-L1 agent, and Platinum-based chemotherapy (e.g., cisplatin or carboplatin), administered either in combination (concurrently) or sequentially (e.g., chemotherapy followed by anti-PD-1/PD-L1 upon progression or as maintenance, or vice versa). Patients must have experienced documented disease progression on or after anti-PD-(L)1 therapy. Patients must not have received any additional systemic therapies for advanced/metastatic NSCLC beyond the above anti-PD-(L)1/platinum-based regimen. Patients who were primary refractory to anti-PD-(L)1 (i.e., no evidence of clinical benefit, defined as progressive disease at first radiologic assessment or no disease control within 12 weeks of treatment initiation) are not eligible. Cohort E2: Patients must have histologically confirmed Stage III or IV urothelial carcinoma and must have received prior systemic therapy meeting all of the following criteria: Prior treatment with an anti-PD-1 or anti-PD-L1 agent, either as monotherapy, in combination with chemotherapy, or in combination with enfortumab vedotin. Patients must have experienced documented disease progression on or after anti-PD-(L)1 therapy. Patients who were primary refractory to anti-PD-(L)1 (i.e., no evidence of clinical benefit, defined as progressive disease at first radiologic assessment or no disease control within 12 weeks of treatment initiation) are not eligible. Prior treatment with enfortumab vedotin. Patients must have experienced documented disease progression on or after enfortumab vedotin treatment. Anti-PD-(L)1 and enfortumab vedotin may have been administered either sequentially or in combination. Prior exposure to platinum-based chemotherapy (cisplatin or carboplatin), administered in any setting (i.e., neoadjuvant, adjuvant, or metastatic). Optional prior treatment with gemcitabine is permitted in any setting (e.g., in combination with platinum, with Padcev, or as part of another regimen).
• Patient understands and voluntarily signs an ICF prior to any study-related assessments/procedures are conducted.
• Patient is able to adhere to the study visit schedule and other protocol requirements.
• Patient is a female of childbearing potential [defined as a sexually mature woman] who 1) has not undergone hysterectomy (the surgical removal of the uterus) or bilateral oophorectomy (the surgical removal of both ovaries) or 2) has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time during the preceding 12 consecutive months)] and is using any adequate form of birth control must: a. have a negative pregnancy test within 1 week before first dose of study drug b. use highly effective method(s) of birth control consistently and correctly during the study and for at least 4 months after the last dose of study drug (See Section 21: Birth control methods which may be considered as highly effective – CTFG Version 1.1) c. agree to not donate eggs (ova, oocytes) for the purposes of assisted reproduction during the study and for at least 4 months after the last dose of study d. agree to no plan to breastfeed and no plan to become pregnant during the study and for at least 4 months after the last dose of study drug
• Patient is a male who is sexually active must: a. agree to use a condom with spermicidal foam/gel/film/cream/suppository during the study and for at least 4 months after the last dose of study drug b. agree to not donate sperm during the study and for at least 4 months after the last dose of study drug c. no plan to father a child during the study or within 4 months after the last dose of study drug
• Patient has histologically and/or cytologically confirmed solid tumors. The following tumor specific restrictions apply for all study parts (please note that specific tumor types may not be eligible for specific study parts and/or cohorts)
• Not applicable to Part E : Breast cancer: a) Patients with hormone-receptor positive (as per local laboratory) recurrent locally advanced or metastatic breast cancer, regardless of HER2 status, must have received at least two prior lines of endocrine therapy in the adjuvant or metastatic setting, either as monotherapy or in combination with targeted therapy as e.g., CDK4/6 or PIK3CA inhibitors. For pre- or peri-menopausal patients LHRH agonists are allowed. b) For patients with recurrent locally advanced or metastatic non-curative HER2 negative breast cancer (based on most recently analyzed biopsy), HER2 status is defined as per ASCO-CAP guidelines as negative, if in situ hybridization test or IHC status is 0, 1+, or 2+. If IHC is 2+, then a negative in situ hybridization (FISH, CISH, or SISH) test is required by local laboratory testing. c) Patients with metastatic triple negative breast cancer are eligible after at least one prior line of cytotoxic chemotherapy and ADCs (unless contraindicated; and if available) and have exhausted available standard therapy options that as per discretion of the investigator may confer relevant clinical benefit. d) Prior adjuvant or neoadjuvant chemotherapy allowed.
• Patient has received a maximum of two prior lines of cytotoxic chemotherapy in the metastatic setting.
• Patient has tumor that is positive for CD205 antigen ( 2+ in ≥ 50% of tumor cells by IHC staining). Once the safety run-ins have been completed and the dose expansion has been opened in the selected schedule(s), then for Part D the SRC (after review of response - CD205 expression correlation data), can decide to reserve up to 30% of slots in a cohort for patients with low CD205 expression (≥ 2+ in between ≥ 25% to < 50% of tumor cells by IHC staining). Note: The CD205 assay is a laboratory developed test, validated in a CAP/CLIA setting, and performed in a central CAP/CLIA certified laboratory. CD205 expression must have been demonstrated either during pre-screening or screening in an archival biopsy, collected within the past 2 years prior to signature of prescreening ICF or main ICF, whichever is earlier; or in a fresh or archival biopsy collected during screening.