Vanderbilt Clinical Trials

Conditions

• Advanced Extrapulmonary Neuroendocrine Carcinoma
• Metastatic Extrapulmonary Neuroendocrine Carcinoma
• Recurrent Extrapulmonary Neuroendocrine Carcinoma
• Unresectable Extrapulmonary Neuroendocrine Carcinoma

Eligibility

Eligible Ages

Over 18 Years

Eligible Genders

All

Accepts Healthy Volunteers

No

Criteria

Inclusion Criteria:

- Participants must have histologically-confirmed (local site pathological
confirmation sufficient) extrapulmonary poorly differentiated, neuroendocrine
carcinoma (NEC)

- Participants must have disease that is unresectable or metastatic and not eligible
for definitive therapy as deemed per the treating investigator

- Participants must have radiologically evaluable disease, measurable or
non-measurable, per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
criteria. All measurable and non-measurable lesions must be assessed by CT scan with
IV contrast of the chest/abdomen/and pelvis (or CT chest without contrast and MRI
abdomen/pelvis with gadolinium contrast, if contraindication to CT iodinated
contrast) within 28 days prior to registration. While may be used for routine
clinical evaluation, PET scans and bone scans alone are not acceptable for disease
assessment while participating in this study. All known sites of disease must be
assessed and documented on the Baseline Tumor Assessment Form

- Participants must have brain MRI (or CT head with contrast if there is
contraindication to MRI brain) if clinically indicated within 28 days prior to
registration. Note: Brain imaging is not required in participants without known
and/or clinical concern for brain metastases. Participants with asymptomatic central
nervous system (CNS) metastases are eligible if one or more of the following apply:

- Participants who have received treatment for brain metastases must have:

- No evidence of radiological progression (by MRI brain or CT head with
contrast if there is contraindication to MRI brain) within 28 days prior
to registration

- Discontinued all corticosteroids at least 14 days prior to registration

- Participants with treatment-naive brain lesions must have:

- No lesion measuring > 2.0 cm in size in any axis

- MRI brain or CT head with contrast (if there is contraindication to MRI
brain) demonstrating no evidence for mass effect, edema, or other
impending neurological compromise within 28 days prior to registration

- No evidence of radiological progression (by MRI brain or CT head with
contrast if there is contraindication to MRI brain) within 28 days prior
to registration

- No need for > 2 mg of dexamethasone (or equivalent of > 10 mg prednisone)
per day at time of registration

- Participants must not have symptomatic central nervous system (CNS) metastases

- Participants must not have known or suspected leptomeningeal disease

- Participants with prior history of non-metastatic (localized/locally advanced
disease) extrapulmonary poorly differentiated NEC may have had prior platinum-based
therapy +/- radiation +/- surgery provided that all therapy was completed >= 6
months prior to registration

- Participants must discontinue denosumab prior to study registration and plan to
replace with a bisphosphonate while on the study

- Participants must not have had prior treatment for advanced or metastatic NEC EXCEPT
one cycle of platinum (carboplatin/cisplatin) + etoposide is allowed prior to
registration. Other chemotherapy regimens are not allowed. For participants with
prostate or urothelial NEC, prior chemotherapy for the non-NEC component (e.g.
adenocarcinoma or urothelial) is allowed as long as such therapy was completed >= 24
weeks prior to registration and participants have recovered from all prior
toxicities to =< grade 1.

- Participants must not have had prior treatment with an anti-PD-1, anti-PD-L1,
anti-PD-L2, CD137 agonists, anti-CTLA-4 agent, or any other immune checkpoint
inhibitors for any neuroendocrine neoplasm. Immune checkpoint inhibitors given for
other cancer indications are allowed provided last therapy was given at least 12
months prior to study registration

- Participants must not have received treatment with systemic immunostimulatory agents
including, but not limited to, interferon and interleukin2 [IL-2] within 4 weeks or
5 half-lives of the drug (whichever is longer) prior to registration

- Participants must not have had history of known severe allergy, anaphylactic, or
other hypersensitivity reactions to chimeric or humanized antibodies, including to
Chinese hamster ovary cell products or to any component of the atezolizumab
formulation, cisplatin, carboplatin, or etoposide

- Participants must not be on active systemic therapy for another cancer with the
exception of hormonal therapy including androgen deprivation therapy (e.g.,
gonadotropin-releasing hormone [GnRH] agonists or antagonists), which can be
continued while participants are receiving protocol therapy. Use of enzalutamide or
apalutamide is permitted after completion of chemotherapy and must be held during
chemotherapy for participants receiving prior to enrollment. Use of darolutamide is
permitted during chemotherapy. Glucocorticoid-containing regimens, including
abiraterone, are not permitted.

- Participants must be >= 18 years of age

- Participants must have a Zubrod performance status of =< 2 within 28 days prior to
registration

- Participants must have a complete medical history and physical exam within 28 days
prior to registration

- Absolute neutrophil count (ANC) >= 1.5 x 10^9 /L (obtained within 14 days prior to
registration. For participants who received a cycle of chemotherapy prior to
registration, at least 21 days must have elapsed between day 1 of platinum +
etoposide and performance of these tests)

- Hemoglobin >= 9.0 g/dl (obtained within 14 days prior to registration. For
participants who received a cycle of chemotherapy prior to registration, at least 21
days must have elapsed between day 1 of platinum + etoposide and performance of
these tests)

- Platelet count >= 100 x 10^9/L (obtained within 14 days prior to registration. For
participants who received a cycle of chemotherapy prior to registration, at least 21
days must have elapsed between day 1 of platinum + etoposide and performance of
these tests)

- Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x
institutional upper limit of normal (ULN) (obtained within 14 days prior to
registration. For participants who received a cycle of chemotherapy prior to
registration, at least 21 days must have elapsed between day 1 of platinum +
etoposide and performance of these tests)

- Serum total bilirubin =< 1.5 x ULN (obtained within 14 days prior to registration.
For participants who received a cycle of chemotherapy prior to registration, at
least 21 days must have elapsed between day 1 of platinum + etoposide and
performance of these tests)

- Adequate renal function as defined by any 1 of the following: 1) Measured creatinine
clearance (CL) > 50 mL/min OR 2) Calculated creatinine CL > 50 mL/min by the
Cockcroft-Gault formula OR by 24-hour urine collection for determination of
creatinine clearance (obtained within 14 days prior to registration. For
participants who received a cycle of chemotherapy prior to registration, at least 21
days must have elapsed between day 1 of platinum + etoposide and performance of
these tests)

- Participants must not have uncontrolled or symptomatic hypercalcemia (> 1.5 mmol/L
ionized calcium or calcium > 12 mg/dL or corrected serum calcium > ULN) within 14
days prior to registration. Participants who have asymptomatic hypercalcemia are
eligible provided that medical therapy to treat the hypercalcemia is planned

- Participants must not have a diagnosis of immunodeficiency nor be receiving systemic
steroid therapy (equivalent of > 20 mg of hydrocortisone per day) or any other form
of immunosuppressive therapy within 14 days prior to registration

- Participants must not have active or history of autoimmune disease or immune
deficiency, including, but not limited to myasthenia gravis, myositis, autoimmune
hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel
disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjogren
syndrome, Guillain-Barre syndrome, or multiple sclerosis with the following
exceptions:

- Patients with a history of autoimmune-related hypothyroidism who are on
thyroid-replacement hormone are eligible for the study

- Patients with controlled type 1 diabetes mellitus who are on an insulin regimen
are eligible for the study

- Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with
dermatologic manifestations only (e.g., patients with psoriatic arthritis are
excluded) are eligible for the study provided all of following conditions are
met:

- Rash must cover < 10% of body surface area

- Disease is well controlled at baseline and requires only low-potency
topical corticosteroids

- No occurrence of acute exacerbations of the underlying condition requiring
psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic
agents, oral calcineurin inhibitors, or high-potency or oral
corticosteroids within the previous 12 months

- Participants must not have history of idiopathic pulmonary fibrosis, organizing
pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, idiopathic
pneumonitis, or evidence of active pneumonitis on screening chest CT scan. NOTE:
History of radiation pneumonitis in the radiation field (fibrosis) is permitted

- Participants must not have significant cardiovascular disease, such as New York
Heart Association class II or greater cardiac disease, myocardial infarction within
3 months prior to registration, unstable arrythmias, or unstable angina

- Participants must not have had a major surgical procedure other than for diagnosis
within 28 days prior to registration. Participant must not plan to receive a major
surgical procedure during the course of protocol treatment. NOTE: Patient port
placement is not considered a major surgery

- Participants must not have severe infections (i.e., Common Terminology Criteria for
Adverse Events [CTCAE] grade >= 2) at time of registration, including but not
limited to hospitalization for complications for infection, bacteremia, or severe
pneumonia

- Participants must not have known active tuberculosis

- Participants with evidence of chronic hepatitis B virus (HBV) infection must have
undetectable HBV viral load, with testing performed as clinically indicated

- Participants with a history of hepatitis C virus (HCV) infection must have been
treated and cured. Participants with active HCV infection who are currently on
treatment must have an undetectable HCV viral load, with testing performed as
clinically indicated

- Participants with known human immunodeficiency virus (HIV)-infection must be on
effective anti-retroviral therapy at time of registration and have undetectable HIV
viral load within 6 months of registration

- Participants must not have prior allogeneic bone marrow transplantation or solid
organ transplant

- Participants must not have received administration of a live, attenuated vaccine
(e.g., FluMist [registered trademark]) within 28 days prior to initiation of study
treatment, during treatment with atezolizumab, and not plan to receive for 5 months
after the last dose of atezolizumab

- Participants must not be pregnant due to the possibility of harm to the fetus.
Individuals who are of reproductive potential must have agreed to use an effective
contraceptive method (with details provided as a part of the consent process) during
the treatment period and for 5 months after the final dose of atezolizumab. A person
who has had menses at any time in the preceding 12 consecutive months or who has
semen likely to contain sperm is considered to be of "reproductive potential." In
addition to routine contraceptive methods, "effective contraception" also includes
refraining from sexual activity that might result in pregnancy and surgery intended
to prevent pregnancy (or with a side-effect of pregnancy prevention) including
hysterectomy, bilateral oophorectomy, bilateral tubal ligation/occlusion, and
vasectomy with testing showing no sperm in the semen

- Participants must be offered the opportunity to participate in specimen banking.
With participant consent, specimens must be collected and submitted via the
Southwest Oncology Group (SWOG) Specimen Tracking System

- Participants must be informed of the investigational nature of this study and must
sign and give informed consent in accordance with institutional and federal
guidelines

Recruiting Locations

Study Contact

Detailed Description

PRIMARY OBJECTIVES: I. Compare the combination of induction platinum/etoposide and atezolizumab followed by maintenance atezolizumab (Arm 1) versus induction platinum/etoposide alone (Arm 3). II. Compare the combination of induction platinum/etoposide and atezolizumab followed by observation (Arm 2) versus induction platinum/etoposide alone (Arm 3). III. Compare the combination of induction platinum/etoposide and atezolizumab followed by maintenance atezolizumab (Arm 1) versus the combination of induction platinum/etoposide and atezolizumab followed by observation (Arm 2). SECONDARY OBJECTIVES: I. To compare overall survival (OS), measured from start of observation/maintenance, across arms. II. To compare progression free survival (PFS) (measured from randomization and measured from start of observation/maintenance) across arms. III. To compare objective response rate (ORR = confirmed and unconfirmed partial response [PR] + confirmed and unconfirmed complete response [CR]) across arms among patients with measurable disease at randomization. IV. To compare clinical benefit rate (CBR = confirmed and unconfirmed PR + confirmed and unconfirmed CR + stable disease [SD]) across arms among patients with measurable disease at randomization. V. To compare duration of response (DOR) across arms. VI. To evaluate the safety and tolerability of each arm. ADDITIONAL OBJECTIVE: I. To bank tumor and blood samples for future biomarker correlative studies. OUTLINE: Patients are randomized to 1 of 3 arms. ARM I: During induction phase, patients receive atezolizumab intravenously (IV) over 30-60 minutes on day 1 of each cycle, carboplatin IV over 30 minutes or cisplatin IV over 60 minutes on day 1 of each cycle, and etoposide IV on days 1-3 of each cycle. Treatment repeats every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity. During maintenance phase, patients receive atezolizumab IV over 30-60 minutes on day 1 of each cycle. Treatment repeats every 21 days for up to 17 cycles in the absence of disease progression or unacceptable toxicity. ARM II: During induction phase, patients receive atezolizumab IV over 30-60 minutes on day 1 of each cycle, carboplatin IV over 30 minutes or cisplatin IV over 60 minutes on day 1 of each cycle, and etoposide IV on days 1-3 of each cycle. Treatment repeats every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity. Patients then undergo observation for 1 year. ARM III: During induction phase, patients receive carboplatin IV over 30 minutes or cisplatin IV over 60 minutes on day 1 of each cycle and etoposide IV on days 1-3 of each cycle. Treatment repeats every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity. Patients then undergo observation for 1 year. Patients in all arms also undergo compute tomography (CT) scan and/or magnetic resonance imaging (MRI) throughout the trial and blood sample collection on study. After completion of study treatment, patients are followed up for 5 years.