PRIMARY OBJECTIVE:
I. To evaluate the safety and tolerability of anetumab ravtansine with the following
combinations in patients with mesothelin positive pancreatic adenocarcinoma.
SECONDARY OBJECTIVES:
I. To assess the preliminary anti-tumor activity of anetumab ravtansine (anetumab) in
combination with nivolumab, nivolumab and ipilimumab, nivolumab and gemcitabine hydrochloride
(gemcitabine) as measured by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
overall response rate (ORR).
II. To characterize the pharmacokinetics (PK) profile of anetumab (apparent diffusion
coefficient [ADC]), total antibody (ADC and cleaved free antibody), DM4 and DM4-Me (S-Methyl
metabolite of DM4).
III. To evaluate the tumor microenvironment and immune changes in tumor and peripheral blood
over the course of treatment to identify predictors of response or resistance to treatment.
IV. To measure the progressive disease (PD) effects of this combination including molecular
and immune biomarkers in tumor biopsies and peripheral blood.
EXPLORATORY OBJECTIVES:
I. To characterize mesothelin, PD-L1, CD3, CD4, CD8 expressions at baseline and after
treatment in mesothelin positive pancreatic cancer patients.
II. To evaluate level of soluble mesothelin and megakaryocyte potentiation factor (MPF) over
the course of treatment and to correlate these biomarkers with clinical outcome.
III. To perform whole exome sequencing (WES) +/- ribonucleic acid sequencing (RNAseq) in the
tumor biopsy specimens and correlation genomic (e.g. mutational burden) and transcriptomic
biomarkers with clinical outcome.
IV. To evaluate mononuclear phagocyte system (MPS) function, Fc-gamma receptors (FcgammaRs)
and hormone and chemokine mediators as methods to evaluate factors affecting the PK and PD of
these agents.
V. To evaluate anti-drug antibody (ADA) titres changes pre and post treatment and correlate
them with PK, toxicity and responses.
OUTLINE: This is a dose-escalation study of anetumab ravtansine. Patients are assigned to 1
of 3 arms.
ARM I: Patients receive anetumab ravtansine intravenously (IV) over 1 hour on day 1 and
nivolumab IV over 30 minutes on day 8 of cycle 1 and on day 1 of subsequent cycles. Treatment
repeats every 21 or 28 days (cycle 1) for up to 17 cycles in the absence of disease
progression or unacceptable toxicity.
ARM II: Patients receive anetumab ravtansine IV over 1 hour on day 1 and nivolumab IV over 30
minutes on day 8 of cycle 1 and on day 1 of subsequent cycles. Patients also receive
ipilimumab IV over 30 minutes on day 8 of cycle 1 and on day 1 of cycles 2-4. Treatment
repeats every 21 or 28 days (cycle 1) for up to 17 cycles in the absence of disease
progression or unacceptable toxicity.
ARM III: Patients receive anetumab ravtansine IV over 1 hour on day 1 and nivolumab IV over
30 minutes on day 8 of cycle 1 and on day 1 of subsequent cycles. Patients also receive
gemcitabine hydrochloride over 30-40 minutes on days 1 and 8. Treatment repeats every 21 or
28 days (cycle 1) for up to 17 cycles in the absence of disease progression or unacceptable
toxicity.
After completion of study treatment, patients are followed up every 8 weeks for up to 100
days, then every 12 weeks thereafter.
Inclusion Criteria:
- Patients must have histologically or cytologically confirmed pancreatic adenocarcinoma
that is metastatic or unresectable or recurrent
- Only subjects with positive mesothelin expression (Ventana mesothelin [MSLN]-
immunohistochemistry [IHC]; Negative=H-score =< 10) are eligible. This is to be
performed centrally. For dose escalation cohorts, patients with mesothelin expression
in >= 5% of tumor cells are eligible. For dose expansion, patients must have moderate
or strong tumor mesothelin expression defined as >= 30% of tumor cells with mesothelin
expression of 2+/3 on immunohistochemical staining
- Patients must have received and either progressed or been intolerant to at least 1
systemic therapy
- Life expectancy of at least 3 months
- Eastern Cooperative Oncology Group (ECOG) performance status score 0-1 (Karnofsky >=
80%)
- Prior anti-cancer treatments are permitted (i.e. chemotherapy, including gemcitabine
and nab-paclitaxel; radiotherapy; hormonal, or immunotherapy with the exception of
anti-CTLA4, anti-PD1/PD-L1, and combination of anti-CTLA4 and anti-PD1/PD-L1)
providing toxicity (except for alopecia) related to prior anti-cancer therapy and/or
surgery have either resolved, improved to baseline or G1
- At least one (1) measurable lesion at baseline by computed tomography (CT) or magnetic
resonance imaging (MRI) as per RECIST version (v)1.1; measurable disease is a
requirement in both dose escalation phase and dose expansion phase
- Note: Measurable lesions may be in an irradiated field as long as there is
documented progression and the lesion(s) can be reproducibly measured
- At least one lesion safely accessible for biopsy unless medically contraindicated;
biopsies are mandatory both in dose escalation and in dose expansion; in dose
escalation and in expansion the following biopsies are optional: at baseline and at
progression; biopsy could be: core needle or excisional or punch biopsy. Irradiated
lesions can be biopsied if tumor growth is confirmed
- Patients must have archival tumor tissue for mesothelin expression and correlative
biomarker studies; subjects must consent to provide tumor blocks or slides and the
availability of the tissue must be confirmed prior to subjects receiving study
medication; if an archived tumor specimen is unavailable or unsuitable for correlative
biomarker studies, a pre-treatment fresh tumor biopsy is required
- Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy
test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours of study
enrollment or randomization; WOCBP must agree to appropriate methods of contraception
for the duration of treatment and for 6 months after completion of treatment; males
who are sexually active with a partner of childbearing potential must agree to
appropriate methods of contraception for the duration of treatment plus 7 months
post-treatment completion; for all male patients, prior to treatment, advice should be
sought for conserving sperm due to the chance of irreversible infertility as a
consequence of treatment; genetic consultation is recommended if the patient wishes to
have children after ending treatment; the investigator or a designated associate is
requested to advise the patient how to achieve highly effective birth control
- Highly effective (failure rate of less than 1% per year) contraception methods
include:
- Combined (estrogen and progesterone containing: oral, intravaginal,
transdermal) and progesterone-only (oral, injectable, implantable) hormonal
contraception associated with inhibition of ovulation
- Intrauterine device (IUD) or intrauterine hormone-releasing system (IUS)
- Bilateral tubal occlusion or vasectomized partner (provided that partner is
the sole sexual partner and has received medical assessment of the surgical
success)
- Sexual abstinence (reliability to be evaluated in relation to the duration
of the clinical trial and the preferred and usual lifestyle of the patient)
- Male patients with a female partner of childbearing potential must use a condom
and ensure that an additional form of contraception is also used during treatment
plus 7 months post-treatment completion.
- Note: a woman is considered WOCBP, i.e. fertile, following menarche and
until becoming postmenopausal unless permanently sterile; permanent
sterilization methods include but are not limited to hysterectomy, bilateral
salpingectomy and bilateral oophorectomy
- A postmenopausal state is defined as no menses for 12 months without an
alternative medical cause; a high follicle stimulating hormone (FSH) level in the
postmenopausal range may be used to confirm a postmenopausal state in women not
using hormonal contraception or hormonal replacement therapy; a man is considered
fertile after puberty unless permanently sterile by bilateral orchiectomy
- Leukocytes >= 3,000/mcL
- Absolute neutrophil count (ANC) >= 1,500/mcL
- Platelets >= 100,000/mcL
- Hemoglobin >= 9 g/dL
- Patients must have not had a transfusion in the 2 weeks preceding this hemoglobin
(Hb) measurement
- Total bilirubin =< institutional upper limit of normal (ULN)
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 3 x institutional ULN
- Creatinine =< institutional ULN OR glomerular filtration rate (GFR) >= 60 mL/min/1.73
m^2 unless data exists supporting safe use at lower kidney function values, no lower
than 30 mL/min/1.73 m^2
- Albumin >= 2.5 mg/dL
- Ability to understand and the willingness to sign a written informed consent document
Exclusion Criteria:
- Participation in another clinical study with an investigational product during the
last 28 days or 5 half-lives prior to study day 1, whichever is shorter; concurrent
enrollment in a non-interventional clinical study or the follow-up period of an
interventional study is allowed
- Untreated central nervous system (CNS) metastatic disease, leptomeningeal disease, or
cord compression; subjects with previously treated brain metastases may participate
provided they are stable (without evidence of progression by imaging for at least six
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 14 days prior to trial treatment
- Evidence of uncontrolled, active infection, requiring parenteral anti-bacterial,
anti-viral or anti-fungal therapy (washout: 7 days prior to cycle 1 day 1 [C1D1])
- Patients are prohibited from receiving the following therapies during the screening
and treatment phase of this trial:
- Antineoplastic systemic chemotherapy or biological therapy
- Radiation therapy
- Note: Radiation therapy to a symptomatic solitary lesion or to the brain may
be considered on an exceptional case by case basis after consultation with
Cancer Therapy Evaluation Program (CTEP); the patient must have clear
measurable disease outside the radiated field; administration of palliative
radiation therapy will be considered clinical progression for the purposes
of determining progression free survival (PFS)
- Live vaccines within 30 days prior to the first dose of trial treatment and while
participating in the trial; examples of live vaccines include, but are not
limited to, the following: measles, mumps, rubella, chicken pox, yellow fever,
rabies, Bacillus Chalmette-Guerin (BCG), typhoid (oral) vaccine, and intranasal
influenza vaccines (e.g., Flu-Mist)
- Current or prior use of systemic immunosuppressive medication (except corticosteroids
at physiological doses, not exceeding 10 mg prednisone-equivalent day) within 10 days
before the first dose of study medication; intranasal, inhaled, topical, or local
steroid injections are allowed; steroids as premedication for hypersensitivity
reactions (i.e. CT scan premedication) are allowed; systemic glucocorticoids used to
modulate symptoms from an event of suspected immunologic etiology are permitted
- Any major surgery within 4 weeks of study drug administration
- Concomitant second malignancies (except adequately treated squamous cell carcinoma
[SCC] or basal cell carcinoma [BCC] skin cancers or in situ bladder, breast or
cervical cancers) within the last 3 years prior to study entry
- Uncontrolled or significant cardiovascular disease, including but not limited to
ongoing or active symptomatic congestive heart failure, uncontrolled hypertension,
unstable angina pectoris, unstable cardiac arrhythmia
- National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE)
version (v)5 >= grade (G)2 peripheral neuropathy (sensory or motor)
- Patients with corneal epitheliopathy and at the discretion of the ophthalmologist any
other eye disorder
- Note: Low grades of superficial punctate keratitis, within the range seen in the
normal population, should not lead to the exclusion of the patient
- Active or prior documented inflammatory bowel disease (i.e. ulcerative colitis)
- Active or prior documented autoimmune disease within the past 2 years
- Note: subjects with vitiligo, Grave's disease, psoriasis not requiring systemic
treatment or hypothyroidism (i.e. following Hashimoto syndrome) stable on hormone
replacement are not excluded
- Recent history or current evidence of bleeding disorder (i.e. any CTCAE G >= 2
hemorrhage/bleeding event within 28 days before the start of treatment)
- Active human immunodeficiency virus (HIV), hepatitis B or C infection; HIV-positive
patients on antiretroviral therapy with undetectable viral load will not be excluded
from the trial; subjects with treated hepatitis B or C with unquantifiable viral loads
and no organ compromise are not excluded
- Any condition that, in the opinion of the investigator, would interfere with
evaluation of study treatment or interpretation of patient safety or study results
- Pregnant women are excluded from this study because of the potential for teratogenic
or abortifacient effects; because there is an unknown but potential risk for adverse
events in nursing infants secondary to treatment of the mother, breastfeeding should
be discontinued for at least 6 months after last dose of study drugs; these potential
risks may also apply to other agents used in this study; should a patient become
pregnant or suspect she is pregnant while she is participating in this study, the
patient should inform the treating physician immediately
- Participants who have had prior organ transplants (i.e. renal, lung, heart) due to the
potential for increased rejection with immunotherapy
- Patients taking strong CYP3A4 inhibitors or strong CYP3A4 inducers within 2 weeks
before the start of study treatment are excluded; consumption of grapefruit or its
juice, and other fruit/juices which are strong CYP3A4 inhibitors within 2 weeks of
study treatment is also not permitted; examples of strong CYP3A4 inhibitors include
the following: indinavir, ritonavir, clarithromycin, itraconazole, ketoconazole,
nefazodone, and saquinavir; examples of strong CYP3A4 inducers include the following:
carbamazepine, rifampin, phenytoin, St. John's wort, and phenobarbital; these lists
are not exhaustive
