Study of OB-002 in Patients With Refractory Metastatic Cancer

Study Overview
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Brief Summary
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This is an open-label, non-randomized trial with OB-002 monotherapy dose escalation followed by a dose expansion in patients with metastatic colorectal, pancreatic, gastric, breast, or urothelial cancer who have progressed on two or more treatment regimens.

Detailed Description
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The dose escalation will use a conventional 3+3 approach, at a minimum of four planned dose levels (0.25, 0.5, 1.0, and 1.5 mg/kg), to establish a maximum tolerated dose (MTD). Additional dose levels may be investigated if PK, pharmacodynamic (PD), safety, and efficacy data indicate higher dose levels may be appropriate. The first patient - sentinel patient - at each dose level will be observed for three days before additional patients can be dosed within the same dose level. The patients will be dosed once weekly (Days 1, 8, 15, and 22) over a 4-week treatment cycle with a 28-day dose-limiting toxicity (DLT) observation period. After a full cohort has completed Day 28 assessments there will be a pause for safety evaluation conducted by the Safety Monitoring Committee (SMC). Once safety data have been reviewed, the SMC will make their recommendations to Orion who will decide whether to proceed to dosing the next dose cohort. Screening may continue during the SMC pause. Once all patients in the highest planned cohort (1.5 mg/kg OB 002) have completed Day 28 assessments, safety, PK, receptor occupancy (RO), and tolerability data will be reviewed to determine which dose level should be expanded or whether an additional dose level is needed. The expanded cohort will enrol 6 patients at the identified dose level. Patients may remain on treatment until disease progression with a follow-up (FU) period of up to 12 months. All adverse events (AEs) and non-invasive tumor assessments will be documented throughout the FU period to characterize the objective response rate (ORR) and, progression-free survival (PFS). Patients that do not complete the DLT observation period for non-DLT reasons will be replaced

Official Title
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A Phase 1b, Open-label, Non-randomized Trial for the Assessment of Safety, Tolerability, and Pharmacokinetics of OB-002 as a Monotherapy in Patients With Refractory Metastatic Colorectal, Pancreatic, Gastric, Breast, or Urothelial Cancer

Conditions
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Metastatic Cancer, Metastatic Colorectal Cancer, Metastatic Pancreatic Cancer, Metastatic Gastric Cancer, Metastatic Breast Cancer, Metastatic Urothelial Carcinoma

Intervention / Treatment
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* Drug: OB-002


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent. Patients at least 18 years of age on the day of providing consent. Patients with accessible metastatic lesions for repetitive biopsy retrieval. Patients with histologically or cytologically confirmed metastatic colorectal, pancreatic, gastric, breast, or urothelial tumors who have progressed or were intolerant after two or more regimens and for whom no standard of care or curative therapy options are available. Patients with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 within 7 days of the start of treatment Patients with evaluable and measurable lesions as per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 Patients with adequate organ function at the time of enrollment as defined below: Neutrophil count ≥1500/mm3 Platelet count ≥7.5 × 105/mm3 Hemoglobin >9.0g/dL (transfusion >2 weeks before testing permitted) Aspartate transaminase (AST), alanine transaminase (ALT) ≤2.5 × the upper limit of normal (ULN) (≤5-times in patients with liver metastasis) Total bilirubin ≤1.5 × ULN Creatinine clearance >60 mL (determined by Cockcroft-Gault Equation) International normalized ratio (INR) ≤1.5 × ULN and partial thromboplastin time (PTT) or activated partial thromboplastin time (aPTT) In women with the potential for pregnancy (including patients with amenorrhea due to medical reasons, such as chemical menopause), after consenting to the study, the patient must agree to use contraception from enrollment and for at least 12 weeks after taking the final dose of the investigational drug. Women with the potential for pregnancy include those who have begun menstruation, who have not undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy, and who have not gone through menopause. Menopause is defined as the consecutive absence of menstrual periods for ≥12 months. Total abstinence is an acceptable mode of contraception. In the case of men, the patient must agree after consenting to the study to use contraception from enrollment and for at least 13 weeks after taking the final dose of the investigational drug (a period of 90 days [the spermatogenesis cycle] is added to 5-times the elimination half-time of I/O agent. Total abstinence is an acceptable mode of contraception. Exclusion criteria: Unwilling to undergo biopsy retrieval during screening (unless an archival sample taken within 3 months before screening is available) and after the fourth infusion of OB-002 Patients who have undergone systemic chemotherapy, radiotherapy, surgery, or hormone therapy <28 days before enrollment, also see exclusion criterion #8. Note: Patients must have recovered from all AEs due to previous therapies to ≤Grade 1 or baseline. Patients with ≤Grade 2 neuropathy may be eligible. If patients received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting study treatment. Patients with a history of CCR5 antagonist therapy (e.g., vicriviroc, maraviroc). Patients with uncontrolled hypertension (systolic blood pressure ≥150 mmHg or diastolic blood pressure ≥90 mmHg) with treatment QTc interval greater than 450 msec (males) or 470 msec (females) Patients with acute coronary syndrome (including myocardial infarction and unstable angina), and with a history of coronary angioplasty or stent placement performed within 6 months before enrollment Patients with a large amount of pleural effusion or ascites requiring more than weekly drainage Patients with a history of (non-infectious) pneumonitis that required steroids or have current pneumonitis. Patients with a ≥Grade 3 active infection according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0 Patients with symptomatic brain metastasis (1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-central nervous system [CNS] disease) Patients with partial or complete gastrointestinal obstruction Patients with interstitial lung disease requiring treatment with systemic steroids or other agents Patients who test positive for either anti-human immunodeficiency virus type 1 (HIV-1) antibodies, hepatitis B surface antigen (HBsAg), or anti-hepatitis C virus (HCV) antibodies with a positive HCV RNA viral load test Patients with concurrent autoimmune disease, or a history of chronic or recurrent autoimmune disease Patients who require systemic corticosteroids equivalent to ≥10 mg prednisone (excluding temporary usage for tests, prophylactic administration for allergic reactions, or to alleviate swelling associated with radiotherapy) or immunosuppressants, or who have received such a therapy <14 days before enrollment in the present study Patients with a history or findings of ≥Grade 3 congestive heart failure according to the New York Heart Association functional classification Patients with a seizure disorder who require pharmacotherapy Persistent proteinuria >3.5 g/24 hours measured by urine protein-creatinine ratio from a random urine sample (≥Grade 3, NCI CTCAE v5.0) Known hypersensitivity to any of the study drugs, study drug classes, or excipients in the formulation Major surgical procedure or significant traumatic injury within 28 days before the start of study medication Non-healing wound, non-healing ulcer, or non-healing bone fracture Patients with evidence or history of any bleeding diathesis, irrespective of severity Any hemorrhage or bleeding event ≥Grade 3 (NCI CTCAE v 5.0) within 4 weeks prior to the start of the study medication Women who are pregnant or breastfeeding, or with the potential for pregnancy unwilling to undergo contraception Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of the study drug

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: A total of up to 36 patients will be screened and 18 enrolled. At least 3 patients at each of the 4 dose levels (0.25, 0.5, 1.0, and 1.5 mg/kg planned) and up to 6 patients at the highest dose(s) if no MTD. An additional 3 patients may be recruited at any of the dose levels to define the dose(s) for further development. Each patient will be enrolled for at least one 28-day cycle of treatment with a FU period of up to 12 months.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: open label OB-002 monotherapy 0.25 mg/kg<br>Dose Level 1 | Drug: OB-002<br>* The patients will be dosed once weekly (Days 1, 8, 15 and 22) over a 4-week treatment cycle with a 28 day dose-limiting toxicity (DLT) observation period.<br>|
| Experimental: open label OB-002 monotherapy 0.5 mg/kg<br>Dose Level 2 | Drug: OB-002<br>* The patients will be dosed once weekly (Days 1, 8, 15 and 22) over a 4-week treatment cycle with a 28 day dose-limiting toxicity (DLT) observation period.<br>|
| Experimental: open label OB-002 monotherapy 1.0 mg/kg<br>Dose Level 3 | Drug: OB-002<br>* The patients will be dosed once weekly (Days 1, 8, 15 and 22) over a 4-week treatment cycle with a 28 day dose-limiting toxicity (DLT) observation period.<br>|
| Experimental: open label OB-002 monotherapy 1.5 mg/kg<br>Dose Level 4 | Drug: OB-002<br>* The patients will be dosed once weekly (Days 1, 8, 15 and 22) over a 4-week treatment cycle with a 28 day dose-limiting toxicity (DLT) observation period.<br>|
| Experimental: open label OB-002 monotherapy expansion cohort<br>Dose Expansion | Drug: OB-002<br>* The patients will be dosed once weekly (Days 1, 8, 15 and 22) over a 4-week treatment cycle with a 28 day dose-limiting toxicity (DLT) observation period.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety: adverse events | Number of patients experiencing adverse events (AEs), serious AEs (SAEs) abnormalities in clinical laboratory tests, vital signs, electrocardiograms (ECGs), and physical exams | From date of screening until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 12 months | 
| Safety: Maximum Tolerated Dose | MTD will be defined on the basis of dose-limiting toxicities (DLTs) | From date of first infusion with 28 days observation period (+/-3 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| (PK) Pharmacokinetics Cmax | To evaluate the multiple-dose pharmacokinetic (PK) profile of OB-002 with maximum observed concentration (Cmax) profile of OB-002 in patients with refractory metastatic colorectal, pancreatic, breast, or urothelial cancer. | samples are collected from first to fourth infusion (period of 28 days +/- 2 days) | 
| (PK) Pharmacokinetics Tmax | To evaluate the multiple-dose pharmacokinetic (PK) profile of OB-002 with time to maximum serum concentration (Tmax) in patients with refractory metastatic colorectal, pancreatic, breast, or urothelial cancer. | samples are collected from first to fourth infusion (period of 28 days +/- 2 days) | 
| (PK) Pharmacokinetics AUC0-t | To evaluate the multiple-dose pharmacokinetic (PK) profile of OB-002 with area under the curve from time 0 to last sampling time (AUC0-t) in patients with refractory metastatic colorectal, pancreatic, breast, or urothelial cancer. | samples are collected from first to fourth infusion (period of 28 days +/- 2 days) | 
| (PK) Pharmacokinetics AUC0 ∞ | To evaluate the multiple-dose pharmacokinetic (PK) profile of OB-002 with area under the curve from time 0 to infinity (AUC0 ∞) in patients with refractory metastatic colorectal, pancreatic, breast, or urothelial cancer. | samples are collected from first to fourth infusion (period of 28 days +/- 2 days) | 
| (PK) Pharmacokinetics t1/2 | To evaluate the multiple-dose pharmacokinetic (PK) profile of OB-002 with terminal half-life (t1/2) in patients with refractory metastatic colorectal, pancreatic, breast, or urothelial cancer. | samples are collected from first to fourth infusion (period of 28 days +/- 2 days) | 
| (PK) Pharmacokinetics Vd | To evaluate the multiple-dose pharmacokinetic (PK) profile of OB-002 with the volume of distribution (Vd) in patients with refractory metastatic colorectal, pancreatic, breast, or urothelial cancer. | samples are collected from first to fourth infusion (period of 28 days +/- 2 days) | 
| (PK) Pharmacokinetics CL | To evaluate the multiple-dose pharmacokinetic (PK) profile of OB-002 with clearance (CL) in patients with refractory metastatic colorectal, pancreatic, breast, or urothelial cancer. | samples are collected from first to fourth infusion (period of 28 days +/- 2 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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solid tumors, CCR5