First-in-Human Dose Escalation Trial of ATRC-101 in Adults With Advanced Solid Malignancies

Brief Title

A Phase 1b Trial of ATRC-101 in Adults With Advanced Solid Malignancies

Official Title

A Phase 1b Dose Escalation and Expansion Trial to Investigate the Safety, Tolerability, Pharmacokinetics, and Biological Activity of ATRC-101 as Monotherapy and in Combination With Other Anticancer Agents in Adults With Advanced Solid Malignancies

Brief Summary

      ATRC-101-A01 is a Phase 1b, open-label dose escalation and expansion trial of ATRC-101, an
      engineered fully human immunoglobulin G, subclass 1 (IgG1) antibody derived from a naturally
      occurring human antibody. The safety, tolerability, PK, and biological activity of ATRC-101
      will be characterized when administered every two weeks (Q2W) or every 3 weeks (Q3W) as a
      monotherapy or in combination with other anticancer agents.
    

Detailed Description

      For the monotherapy cohorts, including the efficacy expansion cohorts, enrollment is
      restricted to adults with inoperable, locally advanced or metastatic breast cancer, NSCLC,
      CRC, ovarian cancer, and acral melanoma, which are all tumor types that have demonstrated
      ATRC-101 immunoreactivity on at least 50% of tested commercially procured archival specimens.

      For the pembrolizumab combination therapy cohort, enrollment is restricted to adults with
      inoperable, locally advanced or metastatic NSCLC, CRC (only MSI-H or dMMR), melanoma (with
      the exception of uveal melanoma), HCC, HNSCC, ESCC, UC or TNBC, that have been treated with
      anti-PD-1 or anti-PD-L1 therapy and have progressed radiographically or have achieved stable
      disease for a minimum of two months and who, in the judgment of their treating physicians,
      could benefit from a combination of ATRC 101 and pembrolizumab.

      For the PLD combination therapy cohort, enrollment is restricted to adult females with
      inoperable, locally advanced or metastatic high-grade serous epithelial ovarian, fallopian
      tube, or primary peritoneal cancer that is platinum resistant, defined as progression during
      or within 6 months of the last dose of platinum-based chemotherapy OR breast cancer that is
      refractory to other standard therapies.

      For target-enriched expansion cohorts, enrollment will be limited to participants with
      pretreatment tumor biopsies demonstrating ATRC-101 target expression above a predefined
      threshold by IHC at a central laboratory. Target-enriched cohorts will include the same tumor
      types as the respective unenriched cohorts.
    

Study Phase

Phase 1

Study Type

Interventional


Primary Outcome

Incidence of DLTs, treatment emergent adverse events (TEAEs), and changes in safety parameters

Secondary Outcome

 Maximum plasma concentration (Cmax) of ATRC-101

Condition

Breast Cancer

Intervention

ATRC-101

Study Arms / Comparison Groups

 ATRC-101 Q3W
Description:  

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Biological

Estimated Enrollment

240

Start Date

February 11, 2020

Completion Date

March 2025

Primary Completion Date

December 2024

Eligibility Criteria

        Inclusion Criteria

          -  Confirmed diagnosis of:

          -  For the monotherapy cohorts: Inoperable, locally advanced or metastatic breast cancer,
             NSCLC, CRC, ovarian cancer, or acral melanoma that is refractory to standard therapy
             or for which no standard therapy exists. Participants who are considered intolerant of
             or ineligible for standard therapy(ies), as well as participants who have been offered
             but refused standard therapy(ies), may also be eligible.

          -  For the pembrolizumab combination therapy cohort: Inoperable, locally advanced or
             metastatic NSCLC, CRC (only MSI-H or dMMR), melanoma (with the exception of uveal
             melanoma), HCC, HNSCC, ESCC,UC, or TNBC with prior or ongoing anti-PD-1 or anti-PD-L1
             treatment and have progressed radiographically or have achieved stable disease for a
             minimum of two months and who, in the judgment of their treating physicians, could
             benefit from a combination of ATRC-101 and pembrolizumab . The anti-PD-1/anti-PD-L1
             therapy must be FDA approved for their cancer indication at the time of screening.
             Patients with the tumor types eligible for monotherapy that are TMB-H, MSI-H or dMMR
             and have had an unsatisfactory response to anti-PD-1/anti-PD-L1 therapy may enroll for
             the pembrolizumab combination, and additional indications that have been identified as
             ATRC-101 target positive and are FDA approved for pembrolizumab may be added following
             discussion with the study Medical Monitor.

               1. Individuals with BRAF mutant melanoma must have received BRAF inhibitors alone or
                  in combination with a MEK inhibitor, if indicated.

               2. Individuals with NSCLC should have received platinum-based therapy unless
                  contraindicated

          -  For the PLD combination therapy cohort: Inoperable, locally advanced or metastatic
             high-grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer
             that is platinum resistant, defined as progression during or within 6 months of the
             last dose of platinum-based chemotherapy OR breast cancer that is refractory to other
             standard therapies.

          -  For ATRC-101 target-enriched expansion cohort(s): Target-enriched cohort(s) will
             include the same tumor types as the respective unenriched cohort(s).

          -  Measurable disease based on RECIST 1.1, as assessed by the local site
             investigator/radiologist. As per RECIST, lesions situated in an area treated with
             radiation or other loco-regional therapy are considered measurable only if progression
             has been demonstrated in such lesions following loco-regional therapy.

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0-1

          -  Adequate organ and marrow function (i.e., without chronic, ongoing growth factor or
             transfusion support) at Screening as defined by the following laboratory parameters
             via central laboratory results:

          -  Absolute neutrophil count (ANC)

               1. For monotherapy and pembrolizumab combination therapy cohorts: ≥ 1000/µL

               2. For PLD combination therapy cohort: ≥ 1500/µL

          -  Absolute lymphocyte count (ALC) ≥ 500/µL

          -  Platelet count ≥ 75,000/µL

          -  Hemoglobin ≥ 9.0 g/dL

          -  PT/INR, aPTT ≤ 1.5 x ULN unless participant is receiving a stable dose of therapeutic
             anticoagulation

          -  Albumin ≥ 3.0 g/dL

          -  Creatinine clearance or eGFR ≥ 30 mL/min as estimated by the Cockcroft-Gault equation

          -  AST/ALT ≤ 2 x ULN. If documented liver metastases, then ≤ 5X ULN

          -  Bilirubin

               1. For monotherapy and pembrolizumab combination therapy cohorts: ≤ 2 x ULN; or
                  bilirubin ≤ 3 x ULN if due to Gilbert's or Crigler-Najjar disease

               2. For PLD combination therapy cohort: ≤ ULN

          -  Available representative tumor specimens in paraffin blocks (preferred) or ≥ 20
             unstained slides (serial sections), with an associated pathology report, obtained
             after last systemic anticancer therapy and within 60 days prior to the planned first
             dose of investigational product (Cycle 1-Day 1). If fewer than 20 unstained slides are
             available, a discussion with the Medical Monitor is required prior to enrollment. If
             an archived sample is not available, participant must have a tumor that is amenable to
             biopsy without unacceptable risk of a major procedural complication and consent to
             have a tumor biopsy. Tumor lesions used for biopsy should not be lesions used as
             RECIST 1.1 target lesions unless there are no other lesions suitable for biopsy. If a
             RECIST target lesion is used for biopsy, the lesion must be ≥ 2 cm in longest
             diameter. Fine-needle aspirates, cell pellets from pleural effusions, ascites, and
             bone metastases are not acceptable.

             a. For the pembrolizumab combination therapy cohort: A biopsy collected within 60 days
             of the planned first dose of investigational product while the participant is
             receiving anti-PD-1/anti-PD-L1 therapy is acceptable.

          -  Women of childbearing potential (WOCBP) and fertile males with partners who are WOCBP
             must use highly effective contraception (per CTFG 2014) from first dose and through 90
             days after final dose of investigational product

          -  Willing and able to provide written informed consent and able to comply with all trial
             procedures

          -  For ATRC-101 target-enriched expansion cohort(s): Enrollment will be restricted to
             participants with an archival tumor biopsy (a pretreatment tumor biopsy obtained
             before consent to participate in the current study was signed) and the biopsy
             demonstrating ATRC-101 target expression above a predefined threshold by IHC at a
             central laboratory inclusion (3-5 unstained slides, serial sections).

               1. If multiple archived tumor biopsies are available, the site should prioritize the
                  most recent biopsy. If multiple biopsies were performed at the most recent time
                  point, the clinical sites should prioritize lesions distinct from the anticipated
                  screening biopsy anatomical site.

               2. All participants, including those enrolled in target-enriched expansion cohorts,
                  will undergo a tumor biopsy during the screening window (screening biopsy). A
                  tumor biopsy obtained before screening but within 60 days prior to planned Cycle
                  1-Day 1 may suffice as a screening biopsy provided no anti-cancer therapy was
                  administered after the biopsy.

        Exclusion Criteria

        Individuals who meet any of the following criteria are not eligible to participate in this
        trial:

          -  Disease that is suitable for local therapy administered with curative intent.

          -  Malignant disease other than the malignancy to be investigated in this trial within
             the last 5 years with the exception of:

               1. basal or squamous cell carcinoma of the skin OR

               2. curatively treated in situ disease OR

               3. localized (non-metastatic) prostate cancer treated with curative intent and
                  undetectable PSA

          -  Autoimmune disease requiring systemic treatment (e.g., with disease modifying agents,
             corticosteroids, or immunosuppressive drugs) in the past 2 years. Hormone replacement
             therapy (e.g., insulin, thyroxine, and replacement-dose hydrocortisone) is not
             considered systemic treatment.

          -  Active or prior paraneoplastic neurologic disorder of the central nervous system (CNS)
             or history of leptomeningeal disease

          -  Prior allogenic hematopoietic or solid organ transplant

          -  Clinically significant cardiovascular disease, e.g., cerebral vascular accident/stroke
             or myocardial infarction, within 6 months prior to first dose of investigational
             product, unstable angina, congestive heart failure (New York Heart Association ≥ Class
             III), or unstable cardiac arrhythmia requiring medication

          -  For the PLD Combination Therapy Cohort:

               1. Any history of documented congestive heart failure (CHF), arrhythmia, or
                  uncontrolled hypertension (systolic BP > 200 mmHg or diastolic BP > 100 mmHg)

               2. Left ventricular ejection fraction measure by echocardiography or multigated
                  radionuclide acquisition (MUGA) below normal limits for the institution

          -  Presence of active, symptomatic, or untreated CNS metastasis; or CNS metastasis that
             requires local directed therapy or increasing doses of corticosteroids within the 2
             weeks prior to the planned first dose of investigational product. Individuals with
             treated and/or asymptomatic CNS disease may be enrolled if neurologically stable over
             the prior 2 weeks (and after consultation with the Medical Monitor) provided there is
             measurable disease (RECIST 1.1) outside of the CNS and there is no ongoing requirement
             for corticosteroids to manage the disease

          -  HIV infection with an AIDS-defining opportunistic infection within the past 12 months
             or with a CD4+ T cell count <350/µL

          -  Hepatitis B surface antigen (HbsAg) positive OR Hepatitis B core antibody (anti-HBc or
             HBcAb) positive and HBV viral load above the lower limit of quantification

          -  Hepatitis C antibody positive with HCV viral load greater than or equal to the lower
             limit of quantification

          -  Infection requiring intravenous antibacterial, antiviral, or antifungal therapy within
             2 weeks prior to the planned first dose of investigational product

          -  Ongoing ≥ Grade 2 toxicity(ies) due to a previously administered anticancer agent with
             the following exceptions:

               1. Grade 2 neuropathy or alopecia

               2. For the monotherapy cohorts: Grade 2 immune-related endocrinopathy attributed to
                  a checkpoint inhibitor and controlled with hormone replacement alone

          -  Treatment with biological agents (including monoclonal antibodies and cytokines)
             within 28 days of the planned first dose of investigational product with the following
             exception:

             a.For the pembrolizumab combination therapy cohort: -Anti-PD-1/anti-PD-L1 treatment
             within 28 days of the planned first dose of investigational product.

          -  Treatment with radiation, chemotherapy or anticancer small molecule therapy within 14
             days or 5 half-lives (whichever is longer) prior to the first dose of investigational
             product. Treatment with nitrosoureas or mitomycin C require a 42-day washout prior to
             the planned first dose of investigational product

          -  For the PLD combination therapy cohort:

               1. Prior treatment with PLD

               2. Prior treatment with doxorubicin or other anthracycline at cumulative doses
                  greater than 300mg/m2.

                  1. Anthracycline equivalent doses: 1 mg Doxorubicin = 1.8 mg Epirubicin = 0.3 mg
                  Mitoxantrone = 0.25 mg Idarubicin

               3. Anthracyclines or anti-HER2 agents, if last dose was administered < 1 year before
                  enrollment

               4. Prior mediastinal irradiation > 3500 cGY

          -  Receipt of any investigational drug or device not otherwise specified above within 28
             days or 5 half-lives (whichever is longer) prior to the planned first dose of
             investigational product

          -  Pregnant or breastfeeding; negative pregnancy status in WOCBP must be confirmed by
             serum pregnancy test at Screening

          -  History of ≥ Grade 3 infusion-related reaction associated with antibody
             administration, or:

               1. For the monotherapy cohorts: Known allergy/intolerance to ATRC-101 or its
                  excipients

               2. For the pembrolizumab combination therapy cohort: Known allergy/intolerance to
                  ATRC-101, anti-PD-1 or anti-PD-L1, , or their excipients

               3. For the PLD combination therapy cohort: Known allergy/intolerance to ATRC-101,
                  doxorubicin, or to the excipients of ATRC-101 or PLD

          -  Major surgery or significant traumatic injury occurring within 28 days prior to the
             planned first dose of investigational product. If major surgery occurred > 28 days
             prior to Cycle 1-Day 1, individual must have recovered adequately from the toxicity
             and/or complications from the intervention prior to Cycle 1-Day 1

          -  Prior treatment with ATRC-101

          -  Intercurrent illness that is either life-threatening or of clinical significance such
             that it might limit compliance with trial requirements, or in the Investigator's
             assessment would place the participant at an unacceptable risk for participation.
             Uncontrolled pleural effusion, pericardial effusion or ascites requiring recurrent
             drainage procedures is exclusionary

          -  Receipt of a live, attenuated vaccine within 28 days of planned Cycle 1-Day 1.
             Examples of live vaccines include, but are not limited to, the following: measles,
             mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus
             Calmette-Guerin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection
             are generally inactivated flu vaccines and are allowed. Intranasal influenza vaccines
             (e.g. FluMist) are live attenuated vaccines and are not allowed.
             Replication-incompetent viral, mRNA, subunit, conjugate, and toxoid vaccines are
             allowed.

          -  COVID-19 (SARS-CoV-2) pandemic consideration: The COVID-19 vaccination should not be
             delayed; however, caution should be exercised when combining vaccination with cancer
             therapy, particularly immunotherapy. The COVID-19 vaccines can cause transient
             lymphadenopathy and potentially impact assessment of disease burden during screening
             and/or on-study. To allow correct interpretation and reduce equivocal findings,
             investigators should discuss with the participant appropriate timing and selection of
             anatomic site of vaccination (alternative) with respect to imaging scans (MRI or CT).
             Screening scans should be acquired before the first dose of a COVID-19 vaccine or 4-6
             weeks after the second dose of the vaccine. Because cancer patients are considered
             vulnerable population, after COVID-19 vaccination there is also a potential for
             heightened immune related adverse events including CRS. Investigators should use
             judgement when evaluating and managing potentially overlapping adverse events and in
             establishing causality with the study treatment (Schönrich and Raftery 2019; Desai et
             al. 2021; Edmonds et al. 2021; Indini et al. 2021)

        For the pembrolizumab combination therapy cohort ONLY:

          -  Experienced ≥ Grade 3 immune related adverse events while on immunotherapy prior to
             enrollment

          -  Have not recovered from Grade 2 immune related adverse events attributed to
             immunotherapy to Grade 1 or baseline prior to enrollment.

          -  NSCLC with epidermal growth factor receptor (EGFR) or anaplastic lymphoma receptor
             tyrosine kinase (ALK) genomic tumor alterations

          -  Isolated intracranial relapse

          -  Interstitial lung disease or active, non-infectious pneumonitis

          -  Signs and symptoms consistent with clinically significant, decreased pulmonary
             function: (1) blood saturation oxygen level (SpO2) < 90% at rest on room air; (2)
             dyspnea at rest (CTCAE v. 5.0 ≥ Grade 3) or supplemental oxygen used to maintain
             adequate oxygenation within 14 days prior to the planned first dose of investigational
             product

          -  Ongoing immune-related toxicity or immune-related toxicity requiring systemic
             corticosteroids for 30 or more consecutive days for a prior immune related adverse
             event before initiation of study treatment

        For the PLD combination therapy cohort ONLY:

        •Prior drug-induced cardiotoxicity, defined as a sustained decrease in the ejection
        fraction (EF) of > 15%.
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Jonathan Benjamin, MD, PhD, 650-453-5279, [email protected]

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT04244552

Organization ID

ATRC-101-A01


Responsible Party

Sponsor

Study Sponsor

Atreca, Inc.


Study Sponsor

Jonathan Benjamin, MD, PhD, Study Director, Atreca, Inc.


Verification Date

June 2022