Description:
This is a First-in-Human Phase IA/IB open label dose escalation study of intravenous (IV)
administration of ONC-392, a humanized anti-CTLA4 IgG1 monoclonal antibody, as single agent
and in combination with pembrolizumab in participants with advanced or metastatic solid
tumors and non-small cell lung cancers.
Title
- Brief Title: Safety, PK and Efficacy of ONC-392 in Monotherapy and in Combination of Anti-PD-1 in Advanced Solid Tumors and NSCLC
- Official Title: Safety, Pharmacokinetics (PK), and Efficacy of ONC-392 as a Single Agent and in Combination With Pembrolizumab in Advanced Solid Tumors and NSCLC: An Open Label Phase IA/IB Study. Preserve CTLA4 Checkpoint Function (PRESERVE-001)
Clinical Trial IDs
- ORG STUDY ID:
ONC-392-001
- SECONDARY ID:
4R44CA250824-02
- SECONDARY ID:
20193108
- NCT ID:
NCT04140526
Conditions
- Non Small Cell Lung Cancer
- Advanced Solid Tumor
- Metastatic Melanoma
- Metastatic Head and Neck Carcinoma
- Metastatic Renal Cell Carcinoma
- Metastatic Colorectal Cancer
- Sarcomas
- Metastatic Prostate Cancer
- Ovarian Cancer
- Small Cell Lung Cancer
- Metastatic Breast Cancer
- Merkel Cell Carcinoma
- Pancreas Cancer
- Gastric Cancer
- Esophageal Cancer
- Gastroesophageal Junction Adenocarcinoma
- Cervical Cancer
Interventions
Drug | Synonyms | Arms |
---|
ONC-392 | A humanized anti-CTLA4 IgG1 monoclonal antibody made by OncoImmune, Inc. | ONC-392 Treatment as single agent |
Pembrolizumab | Keytruda | ONC-392 in combination with pembrolizumab |
Osimertinib | TAGRISSO | ONC-392 in combination with Osimertinib |
Purpose
This is a First-in-Human Phase IA/IB open label dose escalation study of intravenous (IV)
administration of ONC-392, a humanized anti-CTLA4 IgG1 monoclonal antibody, as single agent
and in combination with pembrolizumab in participants with advanced or metastatic solid
tumors and non-small cell lung cancers.
Detailed Description
Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), also known as CD152 (cluster of
differentiation 152), is a cell surface protein receptor that interacts with B7-1 (CD80) and
B7-2 (CD86) to ensure proper function of regulatory T cells and protect host against
autoinflammatory diseases. Anti-CTLA-4 monoclonal antibodies (mAbs) have demonstrated strong
and broad cancer immunotherapeutic effects (CITE) in a variety of preclinical models and are
used clinically both as monotherapy and as part of combination therapy with Nivolumab
(anti-PD-1). However, CTLA-4 monotherapy has more immunotherapy-related adverse effects
(irAEs) than anti-PD-1/PD-L1 therapy. In addition, the rate of severe irAE (Grades 3 and 4)
reached 55% in melanoma patients receiving combination of Ipilimumab and Nivolumab. The
strong irAEs further limit the doses tolerated by cancer patients. Nevertheless, combination
with anti-PD-1 resulted in significantly improved response rates and patient survival in
multiple types of cancer. Furthermore, anti-CTLA-4 antibodies induce long-lasting immunity in
cancer patients. Therefore, CTLA-4 remains an important immunotherapy target, but major
challenges remain in improving both safety and efficacy of anti-CTLA-4 mAbs.
ONC-392 is a highly selective, humanized monoclonal IgG1-kappa isotype antibody against
CTLA-4. The parental clone was identified through in vivo screening in humanized CTLA-4 mouse
model for high anti-tumor efficacy and low autoimmune toxicity. We have recently demonstrated
that ONC-392 is dissociation from CTLA-4 under low pH to allow its escape from lysosomal
degradation and recycle to cell surface. We have provided several lines of evidence for the
notion that a pH-sensitive antibody ONC-392 is not only safer but also more effective in Treg
depletion and tumor rejection than the Ipilimumab, which is pH-insensitive. First, by
preserving CTLA-4 on the cell surface, Onc-392 leaves higher ligand density for better ADCC.
Second, Onc-392 is more efficient in Treg depletion in tumor microenvironment. Third, Onc-392
is significantly more potent in inducing rejection of large tumors.
The study consists of three parts:
(1) The Part A study is a dose-finding rapid titration, Phase I trial of ONC-392 as a single
agent in patients with advanced or metastatic solid tumors with various histology. The aim of
this trial is to define the recommended Phase II dose for ONC-392 monotherapy (RP2D-M). (2)
The Part B study is a dose-finding phase in combination therapies. Part B1 is ONC-392 in
combination with a standard dose of 200 mg pembrolizumab in patients with advanced or
metastatic solid tumors. Part B2 is ONC-392 in combination with a standard dose of oral TKI
Osimertinib in patients with non small cell lung cancer with EGFR mutations.
(3) The Part C consists of 8 different expansion arms. Arms A, B, and C monotherapy expansion
cohorts can be initiated after the RP2D-M is determined. Arms D through H expansion cohorts
can be initiated after the RP2D-C is determined.
1. Arm A Pancreatic Cancer Cohort, ONC-392 monotherapy, will enroll advanced/metastatic
pancreatic cancer patients who have progressive disease after first and second lines of
systemic treatment.
2. Arm B TNBC Cohort, ONC-392 monotherapy, will enroll advanced/metastatic TNBC patients
who have progressive disease after prior systemic treatments, including checkpoint
inhibitor immunotherapy.
3. Arm C NSCLC Mono Cohort, ONC-392 monotherapy, will enroll advanced/metastatic NSCLC
patients with EGFR or ALK mutations who have progressive disease after prior systemic
treatments, including targeted therapy or checkpoint inhibitors.
4. Arm D NSCLC IO Naïve Cohort, ONC-392/Pembrolizumab combination therapy, will enroll
advanced/metastatic NSCLC cancer patients who are treatment naïve, or anti PD (L)1
immunotherapy naïve and PD-L1-positive (PD L1 TPS ≥ 1%).
5. Arm E NSCLC IO R/R Cohort, ONC-392/Pembrolizumab combination therapy, will enroll
advanced/metastatic NSCLC cancer patients who are R/R to prior anti-PD-(L)1
immunotherapy regardless of PD-L1 status.
6. Arm F Mel IO Naïve Cohort, ONC-392/Pembrolizumab combination therapy, will enroll
advanced/metastatic Melanoma patients who are treatment naïve, or checkpoint inhibitor
immunotherapy naive. Prior systemic chemotherapy or targeted therapy are allowed.
7. Arm G Mel IO R/R Cohort, ONC-392/Pembrolizumab combination therapy, will enroll
advanced/metastatic melanoma patients who are R/R to anti-PD-(L)1 immunotherapy or other
forms of combination immunotherapy. Prior treatment with Ipilimumab is allowed. Patients
who have melanoma recurrence under adjuvant immunotherapy are considered to be
immunotherapy refractory.
8. Arm H MCC IO R/R Cohort, ONC-392/Pembrolizumab combination therapy will enroll
advanced/metastatic MCC patients who are R/R to prior immunotherapy or experience cancer
recurrence within 1 year of IO adjuvant treatment.
Trial Arms
Name | Type | Description | Interventions |
---|
ONC-392 Treatment as single agent | Experimental | The Part A study will test ONC-392 intravenous (IV) infusion up to five predefined dose levels: 0.1 mg/kg (cohort 1), 0.3 mg/kg (cohort 2), 1 mg/kg (cohort 3), 3 mg/kg (cohort 4) and 10 mg/kg (cohort 5) of ONC-392 as monotherapy every 21 days (Q3W). The treatment will continue for up to 1 year, or discontinued upon disease progression, or unacceptable toxicity, or voluntary withdraw. The Part A study will determine the maximal tolerable dose (MTD) and the recommended Phase 2 dose in monotherapy (RP2D-M).
In Part C, Arms A, B, and C monotherapy expansion cohorts will further assess the safety and efficacy of ONC-392 in dose level of RP2D-M as monotherapy in pancreatic cancer, triple negative breast cancer and non small cell lung cancer with driver mutations. | |
ONC-392 in combination with pembrolizumab | Experimental | The Part B1 study will test ONC-392 intravenous (IV) infusion, Q3W, in combination with fixed dose of pembrolizumab. The dose for pembrolizumab will be fixed at 200mg/cycle dosed every 21 days (Q3W).
The Part B1 will start at one level below RP2D-M dose for ONC-392 and 200mg of pembrolizumab. When 2 DLTs occur before 6 patients are enrolled, the ONC-392 dose will be decreased to the next dose level until ≤ 1/6 patients treated at that dose develops a DLT. This dose level will be designated RP2D-C.
In Part C, the expansion cohorts Arm D to H will assess the safety and efficacy of ONC-392 in RP2D-C dose level and Pembrolizumab combination therapy in non small cell lung cancer, melanoma and Merkel cell carcinoma. | |
ONC-392 in combination with Osimertinib | Experimental | The Part B2 study will test ONC-392 intravenous (IV) infusion, Q3W, in combination with fixed dose of Osimertinib of 80 mg PO, QD in non small cell lung cancer with EGFR mutations. The Part B2 will start at one level below RP2D-M dose for ONC-392. The goal is to define the RP2D-C-TKI. | |
Eligibility Criteria
Inclusion Criteria:
1. . Patients must have a histological or cytological diagnosis of NSCLC or any other
type of carcinoma or sarcomas, progressive metastatic disease, or progressive locally
advanced disease not amenable to local therapy.
1. In the Part A Phase I dose escalation study of ONC-392 monotherapy, patients with
advanced/metastatic solid tumors of any histology are eligible for participation.
Please note: tumor types of primary interest in this study are malignant
melanoma, renal cell carcinoma, hepatocellular carcinoma, non-small cell lung
cancer, head and neck carcinoma, gastric carcinoma, ovarian carcinoma, colorectal
cancer, any type of sarcoma.
2. In Part B1 dose finding of the ONC-392 plus pembrolizumab combination, patients
with advanced/metastatic solid tumors of any histology that Pembrolizumab has
been approval as standard of care are eligible for participation. Part B2 is for
patients with non small cell lung cancer with EGFR mutations.
3. In Part C, patients with pancreatic cancer, triple negative breast cancer, non
small cell lung cancer, melanoma and Merkel cell carcinoma are eligible.
4. Measurable disease:
i. In Phase IA dose-finding studies (trial A and B), patients may have non-measurable
disease.
ii. In Phase IB expansion cohorts, patients must have measurable disease as defined
per RECIST version 1.1: iii. Tumor mass: Must be accurately measurable in at least 1
dimension (longest diameter to be recorded) with a minimum size of:
1. 10 mm by computed tomography (CT) scan (CT scan slide thickness must be <5 mm),
2. 20 mm by chest X-ray (if clearly defined and surrounded by aerated lung). iv.
Malignant lymph nodes: >15 mm in short axis when assessed by CT scan (CT scan
slice thickness must be <5 mm).
2. Patient is male or female and >18 years of age on day of signing informed consent.
3. Patient must have a performance status of ≤ 2 on the ECOG Performance Scale
4. Patient must have adequate organ function as indicated by the following laboratory
values:
Hematological: Absolute neutrophil count (ANC) ≥1,500 /mcL; Plateletsa ≥100,000 / mcL;
Hemoglobin ≥9 g/dL or ≥5.6 mmol/L- without qualifications; Renal: Serum creatinine
≤1.5 X upper limit of normal (ULN); Hepatic: Serum total bilirubin ≤1.5 X ULN; OR
Direct bilirubin ≤ ULN for patients with total bilirubin levels >1.5 ULN; AST (SGOT)
and ALT (SGPT) ≤2.5 X ULN, OR ≤5 X ULN for patients with active liver metastases
Coagulation: International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5 X ULN
Activated Partial Thromboplastin Time (aPTT) ≤1.5 X ULN
5. Patient has voluntarily agreed to participate by giving written informed consent.
6. Female patient of childbearing potential has a negative urine or serum pregnancy test.
If the urine test is positive or cannot be confirmed as negative, a serum pregnancy
test will be required. The serum pregnancy test must be negative for the patient to be
eligible.
7. Female patients enrolled in the study, who are not free from menses for >2 years, post
hysterectomy / oophorectomy, or surgically sterilized, must be willing to use 2
adequate barrier methods of contraception to prevent pregnancy or to abstain from
heterosexual activity throughout the study, starting with Visit 1 through 30 days
after the last dose of study therapy. Approved contraceptive methods include for
example; intra uterine device, diaphragm with spermicide, cervical cap with
spermicide, male condoms, or female condom with spermicide. Spermicides alone are not
an acceptable method of contraception.
8. Male patients must agree to use an adequate method of contraception starting with the
first dose of study drug through 90 days after the last dose of study therapy.
Exclusion Criteria:
A patient meeting any of the following criteria is not eligible to participate in this
study:
1. Patients who have not recovered to CTCAE ≤ 1 from the AE due to cancer therapeutics.
The washout period for cancer therapeutic drugs (such as chemotherapy, radioactive, or
targeted therapy) is 21 days, and for antibody drug 28 days.
2. Patients who are currently enrolled in a clinical trial of an investigational agent or
device.
3. Patients who are on chronic systemic steroid therapy at doses >10 mg/day
4. Patients who previously had a severe hypersensitivity reaction to another mAb.
5. Patients who have an active infection requiring systemic IV therapy within 14 days of
prior to administration of ONC-392 or combined ONC-392 and Pembrolizumab.
6. Patients who have a history or current evidence of any condition, therapy, or
laboratory abnormality that might confound the results of the study, interfere with
the patient's participation for the full duration of the study, or is not in the best
interest of the patient to participate, in the opinion of the treating Investigator.
7. Patients with known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.
8. Patients who are pregnant or breastfeeding.
9. For the Part B1 and Part C Arm D to H, the patients that are deemed to be not suitable
for Pembrolizumab.
Maximum Eligible Age: | N/A |
Minimum Eligible Age: | 18 Years |
Eligible Gender: | All |
Healthy Volunteers: | No |
Primary Outcome Measures
Measure: | Dose limiting toxicity (DLT) in monotherapy |
Time Frame: | 21 days |
Safety Issue: | |
Description: | The number of subjects who have dose limiting toxicity during the first cycle of study drug, ONC-392, administration. |
Secondary Outcome Measures
Measure: | The serum half life of the study drug, ONC-392, in monotherapy. |
Time Frame: | 12 weeks |
Safety Issue: | |
Description: | To determine the drug concentration in serum samples that are taken in various timepoints during the treatment in order to calculate drug half life. |
Measure: | The serum half life of the study drug, ONC-392, in combination therapy with Pembrolizumab. |
Time Frame: | 12 weeks |
Safety Issue: | |
Description: | To determine the drug concentration in serum samples that are taken in various timepoints during the treatment in order to calculate drug half life. |
Measure: | Objective Response Rate (ORR) |
Time Frame: | 1 year |
Safety Issue: | |
Description: | To determine the objective response rate based on RECIST v1.1. |
Measure: | Progression Free Survival (PFS) |
Time Frame: | 1 year |
Safety Issue: | |
Description: | To determine the progression free survival based on RECIST 1.1 and iRECIST. |
Measure: | Overall Survival (OS) |
Time Frame: | 1 year |
Safety Issue: | |
Description: | To determine the overall survival. |
Details
Phase: | Phase 1 |
Primary Purpose: | Interventional |
Overall Status: | Recruiting |
Lead Sponsor: | OncoC4, Inc. |
Last Updated
July 29, 2021