MC# 20-14 - A Phase I, Multicenter, Open-Label Study to Determine the Safety, Tolerability, Pharmacokinetics, and Preliminary Efficacy of Combination of ABBV-927 with ABBV-368, Budigalimab (ABBV-181) and/ or Chemotherapy in Subjects with Locally Advanced or Metastatic Solid Tumors

  • Agent(s): ABBV-368, ABBV-927, & Budigalimab
  • Disease Type(s): Lung-NSCLC, Breast- Triple Negative
  • Phase(s): I
  • Drug Classification(s): Targeted Therapy, Monoclonal Antibody, Cytotoxic Therapy
  • Molecular Target(s): OX40, PD-1, CD40

Mechanism of Action

  • ABBV-368 selectively binds to and activates OX40.  This may induce the proliferation of memory and effector T-lymphocytes and inhibit the function of T-regulatory cells (Tregs) in the tumor microenvironment (TME).
  • ABBV-927 is a monoclonal antibody that binds to CD40. This induces CD40-dependent signaling pathways, triggers the proliferation and activation of antigen-presenting cells (APCs), and activates T cells.
  • Budigalimab is a monoclonal antibody that targets and binds to PD-1, thereby blocking its binding to the PD-1 ligand, programmed cell death-1 ligand 1 (PD-L1), and preventing the activation of PD-1/PD-L1 downstream signaling pathways.

Purpose

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

  • About the safety and tolerability of the study agents
  • How proteins that indicate the status of your disease are affected with use of the study agents
  • If the combination of study agents prevents or delays tumor growth or shrinks existing tumors
  • How quickly the study agents are removed from the blood stream
  • If research tests can be used in the future to predict who will benefit from the study agents
Inclusion Criteria
  1. Subjects or their legally authorized representative must voluntarily sign and date an informed consent, approved by an independent ethics committee (IEC)/institutional review board (IRB), prior to the initiation of any screening or study-specific procedures
  2. Subjects must consent to provide archived diagnostic formalin-fixed paraffin-embedded (FFPE) tumor tissue, if available. If archived tissue is not available, fresh tumor biopsy is required
  3. Subjects must be at least 18 years old and weigh at least 35 kg
  4. Laboratory values meeting the following criteria within the screening period prior to the first dose of study drug:
    • serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) ≤ 2.5 × the upper limit of normal (ULN).  Subjects with liver metastasis may have an AST and ALT of ≤ 5.0 × the ULN;
    • total bilirubin ≤ 2 × ULN;
    • absolute neutrophil count ≥ 1,500/mm3;
    • platelet count > 100,000/mm3;
    • creatinine clearance ≥ 50 mL/minute (calculated by Cockcroft-Gault formula or 24-hour urine creatinine clearance);
    • prothrombin (PT)/international normalized ratio (INR) and/or activated partial thromboplastin time (aPTT) ≤ 1.5 × normal limits;
    • hemoglobin ≥ 9 g/dL
  5. An ECOG performance status of 0 or 1 and a life expectancy of ≥ 3 months
  6. Are willing or able to comply with procedures required in this protocol
  7. Subject meets the following disease activity criteria:
    • Dose-Escalation:
      • Arm A: Subjects with an advanced solid tumor (not primary central nervous system [CNS] tumors) who have progressed on standard therapies known to provide clinical benefit and/or subjects who have refused or are intolerant of such therapy.  Subjects who are considered ineligible for standard therapies may be eligible for this study on a case-by-case basis after discussion with and agreement from the sponsor.
      • Arm B (NSCLC): Subjects with histologically or cytologically confirmed NSCLC who previously progressed either during or after regimens which include an anti-PD-1 or PD-L1 therapy (if locally available) and a platinum-based regimen in the recurrent or metastatic setting.  In addition, subjects must have received only 1 prior immunotherapy regimen (anti-CTLA-4 combinations given as 1 treatment regimen will be allowed).
        • Subjects who are eligible for treatment with an anti-PD-1 or PD-L1 therapy but have refused available standard-of-care anti-PD-1 or PD-L1 therapy may be eligible for this study
        • Subjects with epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations must have progressed on approved therapy for those aberrations
    • Dose-Expansion:
      • Arms 1, 2, and 3(TNBC): Male or female subjects with histologically or cytologically confirmed breast adenocarcinoma that is estrogen receptor (ER)/progesterone receptor/human epidermal growth factor receptor (HER)2-negative (as defined per American Society of Clinical Oncology [ASCO]/College of American Pathologists [CAP] guidelines) who:
        • Must have disease progression during or after 1 or 2 systemic therapies that included a taxane
        • Are treatment-naïve to immunotherapy which target T-cell co-stimulation (including, but not limited to PD-1, PD-L1, PD-L2, CD137, CTLA-4, CD40, OX40)
        • Have not received prior platinum therapy in the metastatic setting; If having received previous platinum therapy in the adjuvant or neoadjuvant setting, must not have progressed or recurred within 12 months of completing platinum therapy, or received > 1 line of platinum therapy
        • Have provided consent for pre-treatment and on-treatment fresh tumor biopsies.  If an investigator should have a safety concern with a biopsy procedure for a specific subject, the decision and rationale not to perform a biopsy will be documented and the biopsy will not be performed.  At any time the sponsor may mandate that enrollment will be limited to subjects able to provide paired biopsies in order to obtain approximately 9 pairs per Arm.  If adequate samples have been obtained to achieve study exploratory requirements, the sponsor may eliminate the pretreatment and on treatment fresh biopsy requirement.
      • Arm 4 (TNBC): Male or female subjects with histologically or cytologically confirmed TNBC (as defined per American Society of Clinical Oncology [ASCO]/College of American Pathologists [CAP] guidelines) who:
        • have received no previous anti-cancer therapy for TNBC with the following exceptions:
          • Prior taxane therapy for metastatic TNBC is allowed if the patient received ≤ 1 full cycle (i.e., therapy discontinued within 4 weeks for subjects receiving weekly paclitaxel or nab-paclitaxel; therapy discontinued within 3 weeks for subjects receiving paclitaxel or docetaxel every 3 weeks) in the absence of progression, or if taxane therapy for locally advanced or metastatic disease was >12 months prior to C1D1.
          • Prior taxane therapy as adjuvant or neoadjuvant therapy, or to treat locally advanced disease is permitted but must not have progressed or recurred within 12 months of completing therapy, or received > 1 line of taxane therapy in this setting
        • Must be PD-L1 negative on tumor tissue as assessed by Ventana PD-L1 (SP142) IHC Assay with IC < 1% cutoff
          • Prior PD-L1 test results per the Ventana SP142 (CE IVD) IHC assay are acceptable and results must be submitted to the Sponsor before enrollment.  The sponsor will confirm the PD-L1 status at sponsor-designated central lab.
          • If Ventana SP142 IHC assay results are not available, the subject's tumor tissue samples must be tested at sponsor-designated central lab for PD-L1 status prior to enrollment
        • Have provided consent for pretreatment and on-treatment fresh tumor biopsies.  If an investigator should have a safety concern with a biopsy procedure for a specific subject, the decision and rationale not to perform a biopsy will be documented and the biopsy will not be performed.  At any time the sponsor may mandate that enrollment will be limited to subjects able to provide paired biopsies in order to obtain approximately 9 pairs per Arm.  If adequate samples have been obtained to achieve study exploratory requirements, the sponsor may eliminate the pretreatment and on treatment fresh biopsy requirement.
      • Arm 5 (NSCLC): Subjects with histologically or cytologically confirmed NSCLC who previously progressed either during or after regimens which include an anti-PD-1 or PD-L1 therapy (if locally available) and a platinum-based regimen in the recurrent or metastatic setting.  In addition, subjects must have received only 1 prior immunotherapy regimen (anti-CTLA-4 combinations given as 1 treatment regimen will be allowed).
        • Subjects who are eligible for treatment with an anti-PD-1 or PD-L1 therapy but have refused available standard-of-care anti-PD-1 or PD-L1 therapy may be eligible for this study
        • Subjects with EGFR or ALK genomic tumor aberrations must have progressed on approved therapy for those aberrations
  8. Subjects must have measurable disease per RECIST 1.1
  9. No history of inflammatory bowel disease or pneumonitis, regardless of National Cancer Institute (NCI) CTCAE, version 5.0 grade.
  10. No uncontrolled metastases to the CNS.
    • Subjects with brain metastases are eligible provided that evidence of clinical and radiographic stable disease for at least 4 weeks after definitive therapy is given and subjects have not used steroids for at least 4 weeks prior to first dose of the study drug
  11. Subjects with a prior history of or clinically stable concurrent malignancy are eligible for enrollment provided the malignancy is clinically insignificant, no treatment is required, and the subject is clinically stable
  12. No unresolved AEs ≥ Grade 2 (per NCI CTCAE, version 5.0) from prior anticancer therapy except for alopecia.  Subjects with irreversible toxicity that is not reasonably expected to be exacerbated by any of the investigational products may be included (e.g., hearing loss) after consultation with the sponsor.
  13. Subject must not have received any drug targeting the CD40 or OX40 pathway
  14. Subjects who have been previously treated with an anti-PD-1 orPD-L1-targeting agent must not have had during the course of their therapy:
    • any hypersensitivity to the PD-1 or PD-L1-targeting agent
    • any treatment-related toxicity resulting in discontinuation of the PD-1 or PD-L1 targeting agent
  15. No major surgery ≤ 28 days prior to the first dose of study drug or the surgical wound is not fully healed
  16. No evidence of ongoing hemolysis on hemolysis panel (total, direct and unconjugated serum bilirubin, peripheral blood smear, D-dimers and serum haptoglobin) as judged by the investigator
  17. No history of clinically significant uncontrolled condition(s) including but not limited to the following: uncontrolled hypertension; Grade ≥ 3 peripheral neuropathy; active uncontrolled infection; symptomatic congestive heart failure; unstable angina pectoris or cardiac arrhythmia; and psychiatric illness/social situation that would limit compliance with the study
  18. No history of a major immunologic reaction to any IgG-containing agent
  19. No active autoimmune disease requiring therapy within the previous 2 years, with exceptions of vitiligo, type I diabetes mellitus, hypothyroidism, and psoriasis
  20. No history of primary immunodeficiency, bone marrow transplantation, chronic lymphocytic leukemia, solid organ transplantation, interstitial lung disease, or active or latent tuberculosis without completion of standard-of-care treatment
  21. No positive test results for human immunodeficiency virus, or chronic or active hepatitis A, B, or C
    • Subjects who have a history of hepatitis B or C who have undetectable hepatitis B virus deoxynucleic acid (DNA) or hepatitis C virus ribonucleic acid (RNA) after antiviral therapy may be enrolled
  22. No history of clinically significant medical conditions or any other reason that the investigator determines would interfere with the subject's participation in this study or would make the subject an unsuitable candidate to receive study drug
  23. For all females of childbearing potential; a negative serum pregnancy test at the screening visit and a negative serum/urine pregnancy test at baseline prior to the first dose of study drug
  24. Female subjects of childbearing potential must practice at least 1 protocol-specified method of birth control that is effective from study Day 1 through at least 6 months after the last dose of study drug. Female subjects of nonchildbearing potential do not need to use birth control
  25. Female who is not pregnant, breastfeeding, or considering becoming pregnant during the study or for approximately 6 months after the last dose of study drug
  26. If male and subject is sexually active with female partner(s) of childbearing potential, he must agree, from study Day 1 through 6 months after the last dose of study drug, to practice the protocol-specified contraception
  27. Male who is not considering fathering a child or donating sperm during the study or for approximately 6 months after the last dose of study drug
  28. Subject must not have received anticancer therapy including chemotherapy, immunotherapy, radiation therapy, biologic, herbal therapy, or any investigational therapy within a period of 4 weeks or 5 half-lives, whichever is shorter, prior to the first dose of the study drug.  Palliative radiation therapy for painful bony or skin metastasis for 10 fractions or less is not subject to a washout period.
  29. Subject must not have received immunosuppressive medication within 14 days prior to the first dose of the study drug.  The following are exceptions to this criterion:
    • intranasal, inhaled, or topical steroids or local steroid injections (e.g., intraarticular injection)
    • systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or equivalent (except as required for premedication per the investigator's standard practice)
    • steroids as premedication for hypersensitivity reactions (e.g., computed tomography scan premedication) are allowed
  30. Subject must not have received any live vaccine within 4 weeks prior to the first dose of study drug, or expected need of live vaccination during study participation including at least 6 weeks after the last dose of study drug
Exclusion Criteria

Refer to Inclusion Criteria

Location

  • Dallas, TX - Mary Crowley Cancer Research - Medical City
More Info: https://clinicaltrials.gov/ct2/show/NCT03893955

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Re: MC# 20-14