TGFβ has profound local immunosuppressive and immunoexclusion effects in the tumor microenvironment that are integrally involved in the failure of immune checkpoint inhibitors in some tumors. Preclinical data in a variety of models strongly support the study of AVID200 in patients with treatment-refractory advanced and metastatic malignancies as an approach to reducing immunosuppression/exclusion and increasing the activity of immune checkpoint inhibitors.
Active, not recruiting
Phase 1
| Drug | Synonyms | Arms |
|---|---|---|
| AVID200 | TGFβ receptor ectodomain-IgG Fc fusion protein | Dose Level 1: 180 mg/m2 of AVID200 |
TGFβ inhibits local anti-tumor immunity in the tumor microenvironment (TME) and also promotes
the epithelial to mesenchymal transition (EMT) that enhances the metastatic potential of
tumor cells. Cancer-associated fibroblasts (CAFs) are a critical constituent of the TME. As
is the case for fibrosis in other settings, these cells are myofibroblast-like, and respond
to and are activated by tumor-derived TGFβ. CAFs play a critical role in promoting EMT
resulting in increased tumor cell migration and invasion as well as maintaining the TME to
support tumor cell survival. The immunosuppressive role of TGFβ in the TME has been clearly
demonstrated with the activation of CAFs being an important mechanism underlying immune cell
exclusion. Exclusion of immune cells from tumors and local immunosuppression can both be
reversed by AVID200 therapy.
| Name | Type | Description | Interventions |
|---|---|---|---|
| Dose Level 1: 180 mg/m2 of AVID200 | Experimental | Intravenous infusion of AVID200 over 1 hour administered every three weeks. Starting dose for dose escalation. |
|
| Dose Level 2: 550 mg/m2 of AVID200 | Experimental | Intravenous infusion of AVID200 over 1 hour administered every three weeks. |
|
| Dose Level 3: 1100 mg/m2 | Experimental | Intravenous infusion of AVID200 over 1.5 hours administered every three weeks. |
|
Inclusion Criteria:
- Patients with a documented (histologically or cytologically proven) solid tumor
malignancy that is locally advanced or metastatic
- Patients with a malignancy that is currently not amenable to surgical intervention due
to either medical contraindications or non-resectability of the tumor
- Patients with a malignancy that is either refractory to, or the patient is intolerant
of existing therapy(ies) known to provide clinical benefit, or for which no standard
therapy is available
- Patients with measurable or non-measurable disease according to RECIST, v1.1
- Patients with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of
0 or 1 (or equivalent Karnofsky PS), and anticipated life expectancy of ≥ 3 months
- Patients and their partners who are either not of childbearing potential or who agree
to use a highly effective, non-hormonal, method of contraception during the study and
continuing until 4 months after the last dose of study drug); male patients agreeing
to refrain from sperm donation during this period.
- Patients with the ability to understand and give written informed consent for
participation
Exclusion Criteria:
- Patients with an active second malignancy or history of another malignancy within the
last 2 years with the exception of:
- Treated non-melanoma skin cancers
- Treated carcinoma in situ (CIS) of the breast, cervix, bladder, colon,
endometrium, skin (melanoma) provided complete response (CR) was achieved at
least 2 years prior to study and no additional therapy is ongoing or required
during study period with the exception of anti-estrogen/androgen therapy or
bisphosphonates
- Controlled, superficial carcinoma of the bladder
- T1a carcinoma of the prostate comprising < 5% of resected tissue and prostate
specific antigen (PSA) within normal limits (WNL) since resection
- Any antineoplastic agent for the primary malignancy (standard or investigational),
without delayed toxicity, within 4 weeks or 5 plasma half-lives, whichever is
shortest, prior to C1/D1 and during study with the exception of:
-Nitrosoureas and mitomycin C within 6 weeks prior to C1/D1 and during study
- Any other investigational treatments within 4 weeks prior to and during study;
includes participation in any medical device or supportive care therapeutic
intervention trials
- Radiotherapy for target lesions within 4 weeks prior to C1/D1 and during study;
radiotherapy for non-target lesions within 2 weeks prior to C1/D1
- Radiotherapy within 2 weeks prior to C1/D1 and during study. Patients must have
recovered from all radiation-related toxicities, not require corticosteroids, and not
have had radiation pneumonitis.
- Use of live vaccines against infectious diseases 4 weeks prior to C1/D1 and during
study
- Immunosuppressive or systemic hormonal therapy (> 10 mg daily prednisone or
equivalent) within 2 weeks prior to C1/D1 and during study
- Prophylactic use of hematopoietic growth factors within 2 weeks prior to C1/D1 and
during Cycle 1 of study; thereafter prophylactic use of growth factors is allowed as
clinically indicated
| Maximum Eligible Age: | N/A |
| Minimum Eligible Age: | 18 Years |
| Eligible Gender: | All |
| Healthy Volunteers: | No |
| Measure: | Incidence of Treatment-Emergent Adverse Events |
| Time Frame: | From date of treatment until the date of first documented progression or date of death from any cause, whichever came first, for up to 24 months |
| Safety Issue: | |
| Description: | Number of participants with treatment-related adverse events as assessed by CTCAE v5.0 |
| Phase: | Phase 1 |
| Primary Purpose: | Interventional |
| Overall Status: | Active, not recruiting |
| Lead Sponsor: | Formation Biologics |
December 19, 2020
