Inclusion Criteria:
- - Male or female age ≥ 18 years at the time of informed consent.
- - Be capable, willing, and able to provide written informed consent.
- - Be willing to comply with clinical trial instructions and requirements, including
tumor biopsies (if feasible and required per protocol).
- - Patients must have a locally advanced or metastatic cancer, a malignant solid tumor
that has progressed on at least one line of systemic therapy or for which no standard
treatment is available, or the participant is intolerant to available treatment.
- - In the dose escalation phase study patients must have a histologically or
cytologically confirmed malignant solid tumor that has progressed on at least one
prior standard of care systemic therapy, where available, or declined standard of care
systemic therapy.
- - In the dose expansion phase patients must have a histologically or cytologically
confirmed antiPD1/PD-L1 undifferentiated pleomorphic sarcoma or myxofibrosarcoma,
angiosarcoma, or bone sarcoma or merkel cell carcinoma.
Patients with UPS/MFS,
angiosarcoma and MCC must have progressed on or be refractory to anti-PD-1/anti-PD-L1
therapy.
- - In the dose escalation phase an upper bound weight limit restriction will be used for
dose levels 5 and 6.
Hence, patients must weight ≤90kg and ≤70kg in order to be
eligible to enroll in dose level 5 and 6 of the dose escalation phase, respectively.
- - Adequate performance status: ECOG 0 or 1/KPS 100-70%.
- - Life expectancy of at least three months after the first CRD3874 infusion, according
to the Investigator's opinion.
- - Presence of measurable disease per RECIST v1.1.
Target lesion(s) must not be chosen
from a previously irradiated field unless there has been radiographically and/or
pathologically documented tumor progression in that lesion prior to enrollment.
- - In the dose expansion phase , participants must agree to have a pretreatment tumor
biopsy for research purposes.
Participants in whom biopsy is technically not feasible
or in whom the associated procedure would result in unacceptable risk, in the opinion
of the Investigator, or patients who do not wish to have a biopsy, archival tissue
(most recently procured sample where tissue is available) may be used instead, if
available.
- - In the dose expansion phase , participants must agree to on-treatment tumor biopsy for
research purposes.
Participants in whom biopsy is technically not feasible or in whom
would result in unacceptable risk, in the opinion of the Investigator, or patients who
do not wish to have a biopsy- may be exempted from the biopsy requirement with
discussion with the Principal Investigator .
- - Female subject of childbearing potential (defined as a sexually mature female who has
not undergone a hysterectomy or bilateral oophorectomy or who has not been naturally
postmenopausal for at least 24 consecutive months) should have a negative serum
pregnancy testing at screening visit and within 72 hours prior to the first dose of
study medication.
- - Adequate organ function determined within 14 days of treatment initiation, defined as
follows:
- Hemoglobin ≥ 9.0 g/dL.
- - Absolute neutrophil count ≥ 1,000/mm^3 (1.0 x 10^9/L)
- Platelet count ≥ 100,000/mm3 (100 x 10^9 /L)
- Serum bilirubin ≤ 1.2x upper limit of normal (ULN) OR direct bilirubin ≤ ULN for
participants with total bilirubin level > 1.2x ULN.
- - Aspartate aminotransferase (AST) ≤ 2.5x ULN OR ≤ 5x ULN for participants with
liver metastases.
- - Alanine aminotransferase (ALT) ≤ 2.5x ULN OR ≤ 5x ULN for participants with liver
metastases.
- - Calculated creatinine clearance (CrCl) ≥ 60 mL/min by Cockcroft-Gault formula.
- - International Normalized Ratio (INR) or prothrombin time (PT) ≤1.5x ULN unless
participant is receiving anticoagulant therapy as long as PT or partial
thromboplastin time (PTT) is within therapeutic range of intended use of
anticoagulants.
- - Activated partial thromboplastin time (aPTT) ≤ 1.5x ULN unless participant is
receiving anticoagulant therapy as long as PT and PTT is within therapeutic range
of intended use of anticoagulants.
- - Left ventricular ejection fraction (LVEF) > 50%, as measured by echocardiogram
(2D-ECHO) or multi-gated acquisition scan (MUGA)
Exclusion Criteria:
- Known prior severe hypersensitivity to an investigational product or any component of
the study drug therapy's formulations including polyethylene glycol (PEG), (NCI CTCAE
v5.0 Grade ≥ 3)
- Evidence of clinically significant immunosuppression such as the following:
- Primary immunodeficiency state such as Severe Combined Immunodeficiency Disease.
- - Concurrent opportunistic infection.
- - Receiving systemic immunosuppressive therapy (> 2 weeks) including oral steroid
doses > 10 mg/day of prednisone or equivalent within 7 days prior to enrollment.
In the setting of non-immune mediated indications for use, chronic/active low
dose steroid (equivalent to
- Current use of immunosuppressive medication, EXCEPT for the following:
I.Intranasal, inhaled, ocular, topical steroids, or local steroid injection (e.g.,
intraarticular injection)
- II. Systemic corticosteroids at physiologic doses ≤ 10 mg/day of
prednisone or equivalent III.
Steroids as premedication for hypersensitivity reactions
(e.g., CT scan premedication)
- - Prior organ transplantation, including allogenic stem-cell transplantation.
Consideration will be given to allow patients with a history of autologous
transplantation enroll if they are at least 5 years beyond the completion of the
transplant pending discussion with the principal investigator.
- - History or evidence of symptomatic autoimmune disease (e.g., pneumonitis,
glomerulonephritis, vasculitis, or other), or history of active autoimmune disease
that has required systemic treatment (i.e., use of corticosteroids, immunosuppressive
drugs or biological agents used for treatment of autoimmune diseases) in past 2 years
prior to enrollment.
Replacement therapy (e.g., thyroxine for hypothyroidism, insulin
for diabetes or physiologic corticosteroid replacement therapy for adrenal or
pituitary insufficiency) is not considered a form of systemic treatment for autoimmune
disease.
- - Systemic antibiotics received ≥ 7 days prior to the first dose of study drugs.
- - Uncontrolled medical condition including current active infection requiring systemic
therapy or symptomatic congestive heart failure within 6 months that in the
investigators opinion compromise the ability of the patient to complete all study
related requirements safely.
- - Inability to comply with protocol required procedures.
- - Mean resting corrected QT interval ≥ 470 ms on a 12-lead electrocardiogram (ECG) for
males and females.
- - Is currently participating and receiving study therapy or has participated in a study
of an investigational agent and received study therapy or used an investigational
device within 4 weeks of the first dose of treatment or 5 half-lives, if shorter.
- - Has had prior chemotherapy or targeted small molecule therapy within 3 weeks,
anti-cancer monoclonal antibody (mAb) within 4 weeks or OR 5 half-lives, if shorter,
or radiation therapy within 2 weeks prior to the first CRD3874 infusion prior to study
Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events
due to a previously administered agent.
- - Note: Alopecia or other Grade ≤ 2 not constituting a safety risk based on
investigator's judgment are acceptable.
- - Note: If patient received major surgery, they must have recovered adequately from
the toxicity and/or complications from the intervention prior to starting study
therapy.
- - Evidence of clinically significant interstitial lung disease, history of interstitial
lung disease, or active, noninfectious pneumonitis related to prior immunotherapy
treatment.
- - History of unstable or deteriorating cardiovascular disease within the previous 6
months prior to screening including but not limited to the following:
- Unstable angina or myocardial infarction.
- - Congestive heart failure (New York Heart Association [NYHA] Class III or IV.
- - Uncontrolled clinically significant arrhythmias.
- - Has known active central nervous system (CNS) metastases and/or carcinomatous
meningitis.
- - Patients with previously treated brain metastases or carcinomatous meningitis may
participate provided they are stable (without evidence of progression by imaging for
at least four weeks prior to the first dose of trial treatment and any neurologic
symptoms have returned to baseline), have no evidence of new or enlarging brain
metastases, and are not using steroids for at least 7 days prior to trial treatment.
- - Has received a live vaccine within 30 days of the planned start of study drug.
Note:
Seasonal influenza vaccines for injection are generally inactivated flu vaccines and
are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live
attenuated vaccines, and are not allowed.
- - Patients known to be positive for active Hepatitis B (HBsAg reactive with detectable
HBV DNA), or Hepatitis C (HCV RNA (qualitative) is detected)
1.
Patients with chronic hepatitis B (positive HBsAg and/or HBcAb and negative HBV
DNA by PCR) are eligible for this study if they are on suppressive anti-viral
therapy and deemed safe by a gastroenterologist. 2. Patient who is HCV Ab positive but HCV RNA negative due to prior treatment or
natural resolution will be considered eligible.
- - Known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies) disease that
is not controlled.
Note HIV-positive patients will be considered eligible if:
- - Established ART for at least four weeks and have an HIV viral load less than 400
copies/mL prior to enrollment.
- - CD4+ T-cell (CD4+) counts ≥ 350 cells/uL.
- - No opportunistic infection within the past 12 months.
- - Has a known history of active TB (Bacillus Tuberculosis)
- Women who are pregnant or breastfeeding.
- - Patients expecting to conceive or father children within the projected duration of the
trial, starting with the pre-screening or screening visit through three months after
the last dose of study treatment(s).
- - Female participants of childbearing potential and male participants who are unwilling
to use acceptable method(s) of effective contraception during study treatment and
until six months for female and three months for males after the last dose of
CRD3874-SI.
Abstinence is acceptable if this is the usual lifestyle and preferred
contraception for the participant.
(Note: Women not of childbearing potential are defined as: Any female who is postmenopausal
[age > 55 years with cessation of menses for 12 or more months or less than 55 years but
with no spontaneous menses for at least two years or less than 55 years and spontaneous
menses within the past one year but currently amenorrheic (e.g., spontaneous or secondary
to hysterectomy) and with postmenopausal gonadotropin levels (luteinizing hormone and
follicle-stimulating hormone levels > 40 IU/L) or postmenopausal estradiol levels (< 5
ng/dL) or according to the definition of "postmenopausal range" for the laboratory
involved] or who have had a hysterectomy, bilateral salpingectomy, or bilateral
oophorectomy.)
- - The presence of a concurrent active malignancy that in the opinion of the investigator
could compromise the conduct of the study or interfere with determining the outcomes
of the study objectives.
