MC# 19-17 - A Phase I, Open-Label, Dose Escalation and Expansion Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Preliminary Anti-tumor Activity of PSB205 in Patients with Relapsed/Refractory Solid Tumors

  • Agent(s): PSB201
  • Disease Type(s): Solid Tumor
  • Phase(s): I
  • Drug Classification(s): Targeted Therapy, Immunotherapy, Monoclonal Antibody
  • Molecular Target(s): PD-1, CTLA4

Mechanism of Action

PSB205 is a bifunctional product that contains a fixed-ratio mixture of anti-PD-1 and anti-CTLA-4 monoclonal antibodies, produced by a single cell line.

Purpose

In this study, the sponsor and investigators want to learn:

  • How much of PSB201 can be given with an acceptable level of side effects
  • About the safety and tolerability of PSB201
  • How proteins that indicate the status of your disease are affected with use of PSB201
  • How much of PSB201 is absorbed into the blood and how fast it is removed
  • If your body develops proteins that work against PSB201
Inclusion Criteria
  1. Male or female subjects aged 18 years or older
  2. Eastern Cooperative Oncology Group (ECOG) performance status ≤2. Inclusion of subjects with an ECOG performance status of 2 should be discussed and is at the discretion of the sponsor’s medical monitor and the investigator
  3. Life expectancy of ≥3 months
  4. Clinical laboratory values and other measures need to be as specified in the outline below within 28 days before the first dose of study drug:
    • Absolute neutrophil count (ANC) in the absence of growth factor support ≥1.5x109/L
    • Platelets ≥100,000/µL
    • Hemoglobin ≥9 g/dL
    • AST and ALT ≤2.5 x ULN unless liver metastases are present, in which case they must be ≤5 x ULN
    • Total bilirubin ≤1.5 x ULN unless Gilbert’s syndrome is known, in which case they must be ≤3 x ULN
    • Serum creatinine ≤1.5 x ULN or calculated creatinine clearance (CrCl) ≥30 mL/min using Cockcroft-Gault equation for subjects with creatinine levels >1.5 x institutional ULN
  5. Female subjects who are not pregnant or breastfeeding and who:
    • Are surgically sterile, OR
    • Are postmenopausal for at least 1 year before the Screening visit, OR
    • If they are of childbearing potential, agree to practice one highly effective method of contraception and one additional effective (barrier) method, at the same time from the time of signing the informed consent through 180 days after the last dose of study drug, OR
    • Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (eg, calendar, ovulation, symptothermal, postovulation methods), withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together.
  6. Male subjects, even if surgically sterilized (ie, status post-vasectomy), who
    • Agree to practice effective barrier contraception during the entire study treatment period and through 180 days after the last dose of study drug, OR
    • Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (eg, calendar, ovulation, symptothermal, postovulation methods), withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together.
  7. Willing and able to comply with protocol-specified activities
  8. Voluntary written consent must be given before performance of any study-related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care
  9. Suitable venous access for the study-required blood sampling, including PK and PD sampling
  10. Recovered (ie, ≤Grade 1 toxicity) from all reversible AEs of previous anticancer therapies to Baseline or CTCAE v5.0 Grade 1, except for alopecia (any grade) and Grade ≤2 sensory peripheral neuropathy, hypomagnesemia or lymphopenia, within 14 days prior to dosing the first dose. Inclusion of subjects with other non-clinically significant (Grade ≤2) toxicities should be discussed and approved by the sponsor’s medical monitor and the investigator
  11. To be enrolled in Part 1 (Dose escalation), subjects must have:
    • Histologically confirmed diagnosis of advanced solid tumor with a radiographically or clinically measurable disease
    • No curative options and progressed on or following standard of care therapy. Note: For Part 1a, non-measurable evaluable disease is permitted.
  12. To be enrolled in the Part 2 (Dose Expansion), subjects must be eligible for one of the three cohorts described below. Note that measurable disease is as defined by RECIST Version 1.1 or iRECIST. Tumor lesions that are situated in a previously irradiated (or other locally treated) area will be considered measurable, provided that there has been clear imaging-based progression of the lesions since the time of radiation.

Cohort 1: Locally advanced or metastatic squamous NSCLC or HNSCC not amenable to curative therapy. Subjects must have progressed on or after at least 1 prior platinum-based therapy regimen and 1 prior therapy with a US FDA- approved single agent PD-1/PD-L1 inhibitor. Subjects with NSCLC with EGFR, ALK, ROS-1, or BRAF V600E genomic tumor aberrations must have had disease progression on FDA-approved therapy for the genomic aberration.

Cohort 2: Locally advanced or metastatic gastric or gastroesophageal carcinoma not amenable to curative therapy. Subjects must have progressed on or after at least 2 prior systemic therapy regimens including, if appropriate, cisplatin- fluoropyrimidine-based regimen, ramucirumab as a single agent or in combination with paclitaxel, trifluridine/tipiracil, and pembrolizumab for PD-L1 positive tumors. Prior therapy must have included trastuzumab or another HER2 active agent if the subject has HER2 positive disease. Patients whose tumors express PD-L1 [combined positive score ≥1] as determined by an FDA-approved test must also have received pembrolizumab.

Cohort 3: Subjects in Cohort 3 must have one of the following solid tumors:

  • Locally advanced or metastatic ccRCC or non-clear cell RCC not amenable to curative therapy. Subjects with ccRCC must have received at least 2 prior systemic therapies for locally advanced or metastatic disease and be deemed by the investigator as unlikely to benefit from further standard therapy. Subjects with non-clear cell RCC must have received at least 1 prior therapy for locally advanced or metastatic disease and be deemed by the investigator as unlikely to benefit from further standard therapy. Subjects with ccRCC or non-clear cell RCC may have received a PD-1/PD-L1 inhibitor provided they have not also received a concurrent CTLA-4 inhibitor.
  • Advanced urothelial cancer not amenable to curative therapy. Subjects must have received at least 1 systemic therapy regimen for locally advanced or metastatic disease and be deemed by the investigator as unlikely to benefit from additional standard therapy. Subjects may have received a PD-1/PD-L1 inhibitor provided they have not also received a concurrent CTLA-4 inhibitor.
  • Small cell lung cancer not amenable to curative therapy. Subjects must have received at least 2 prior systemic therapy regimens and be deemed by the investigator as unlikely to benefit from additional standard therapy.
    • Subjects may have received a PD-1/PD-L1 inhibitor provided they have not also received a concurrent CTLA-4 inhibitor.
  • Advanced soft tissue or bone sarcoma not amenable to curative therapy. Subjects with sarcoma must not have received prior therapy with either a PD-1/PD-L1 or CTLA-4 inhibitor.
  • Metastatic melanoma not amenable to curative therapy. Subjects must have received at least 1 systemic therapy regimen for locally advanced or metastatic disease and be deemed by the investigator as unlikely to benefit from additional standard therapy. Subjects may have received a PD-1/PD-L1 inhibitor provided they have not also received a combination of a PD-1/PD-L1 and a concurrent CTLA-4 inhibitor.
  • Mismatch-repair-deficient malignancies not amenable to curative therapy and deemed by the investigator as unlikely to benefit from additional standard therapy. Subjects may have received a PD-1/PD-L1 inhibitor provided they have not also received a concurrent CTLA-4 inhibitor.
Exclusion Criteria
  1. Active or prior documented autoimmune disease (including inflammatory bowel disease, celiac disease, Wegener syndrome) within the past 2 years. Subjects with childhood atopy or asthma, vitiligo, alopecia areata, Hashimoto syndrome, Grave’s disease, or psoriasis not requiring systemic treatment (within the past 2 years) are not excluded.
  2. Grade 3 or Grade 4 irAEs related to prior cancer immunotherapy
  3. Untreated central nervous system metastatic disease, leptomeningeal disease, or cord compression. Subjects previously treated central nervous system metastases that are radiographically and neurologically stable for at least 6 weeks and do not require corticosteroids (of any dose) for symptomatic management for at least 14 days prior to first dose of study drug are permitted to enroll.
  4. Hypertension unable to be controlled to ≤Grade 2 with medication
  5. Any condition requiring systemic treatment with corticosteroids (>10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days before first dose of study drug. Corticosteroids for topical use, nasal spray, and inhaled steroids are allowed. Systemic corticosteroids for prophylaxis of contrast allergy are permitted.
  6. Prior treatment with a CTLA-4 inhibitor in combination with a PD-1 or PD-L1 inhibitor
  7. Systemic anti-cancer treatment (including investigational agents). This includes radiotherapy <2 weeks before the first dose of study drug, ≤4 weeks for
    • antibody-based therapy including unconjugated antibody, antibody-drug conjugate, and bi-specific T cell engaging agents; (≤8 weeks for cell-based therapy or
    • anti-tumor vaccine) or have not recovered from acute toxic effects from prior chemotherapy and radiotherapy.
  8. Major surgery within 14 days before the first dose of study drug and not recovered fully from any complications from surgery
  9. Subjects with a history of organ transplant
  10. Systemic infection requiring IV antibiotic therapy or other serious infection within 14 days before the first dose of study drug
  11. Hepatitis B surface antigen-positive or known or suspected active hepatitis C infection
  12. Known human immunodeficiency virus (HIV) positive
  13. Subjects with any of the following cardiovascular conditions are excluded:
    • Acute myocardial infarction within 6 months before first dose of study drug
    • Current or history of New York Heart Association Class III or IV heart failure
    • Evidence of current uncontrolled cardiovascular conditions including cardiac arrhythmias, angina, pulmonary hypertension, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities
    • Fridericia corrected QT interval (QTcF) >450 msec (men) or >470 msec (women) on a 12-lead ECG during the screening period
  14. Clinically significant 12-lead ECG abnormalities at screening
  15. Active interstitial lung disease (ILD) or pneumonitis or a history of ILD or pneumonitis requiring treatment with steroids or other immunosuppressive medications
  16. Subject has a history of alcoholism or drug abuse within the past 6 months
  17. Subject has used medications within 2 weeks of first dose of study drug that may affect the safety or other study assessments, in the opinion of the investigator
  18. Vaccinations within 4 weeks of first dose of study drug. The inactivated seasonal influenza vaccine can be given to subjects before treatment and while on therapy without restriction. Influenza vaccines containing live virus or other clinically indicated vaccinations for infectious diseases (eg, pneumovax, varicella, shingles) may be permitted but must be discussed with the Medical Monitor and may require a washout period before and after administration of vaccine.
  19. Subjects with microsatellite instability high solid tumors who have not received prior therapy with a PD-1 inhibitor

Location

  • Dallas, TX - Mary Crowley Cancer Research - Medical City
More Info: https://clinicaltrials.gov/ct2/show/NCT03986606

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Re: MC# 19-17