Background:
Less toxic and more effective treatments are needed for cancers caused by viruses. These
cancers include Hodgkin and non-Hodgkin lymphoma, hepatocellular carcinoma, head and neck
cancer, nasopharyngeal carcinoma, gastric cancer, anal cancer, cervical cancer, vaginal
cancer, vulvar cancer, penile cancer, Merkel cell carcinoma, Kaposi sarcoma, and
leiomyosarcoma. Researchers want to see if a combination of drugs can help.
Objective:
To find a safe dose of pomalidomide plus nivolumab in people with cancers caused by viruses.
Eligibility:
Adults ages 18 or older who have cancers caused by Epstein Barr virus (EBV), human herpes
virus 8/Kaposi sarcoma herpesvirus (HHV8/KSHV), human papilloma virus (HPV), hepatitis B or C
virus (HBV/HCV), and Merkel cell polyomavirus (MCPyV) that have not responded to previous
treatments or have relapsed, or in adults who do not want to have surgery because of
disfigurement or other risks. Adults who have HIV with any CD4 T cell count are eligible.
Design:
Participants will be screened with blood and urine tests, scans, and heart tests. They will
have a physical exam. Their ability to perform normal daily activities will be assessed. They
may have a tumor biopsy.
Treatment will be given in 28-day cycles. Participants will take pomalidomide as a tablet by
mouth for 21 days of each cycle, for up to 24 cycles. They will get nivolumab by intravenous
infusion once each cycle. They will take an aspirin each day until 30 days after their last
dose of the study drugs.
Participants will keep a pill diary. They will bring it to their study visit at the end of
each cycle. At these visits, some screening tests will be repeated. Participants with Kaposi
sarcoma will have pictures taken of their lesions.
Participants will give blood and saliva samples for research. They may have optional anal
and/or cervical swabs. They may have optional biopsies.
Participants will have a follow-up visit 30 days after they stop taking the study drugs, then
every month for 100 days. Some screening tests will be repeated. Then they may by contacted
by phone every 3 months for 9 months, and then every 6 months thereafter....
Background:
- There is an unmet need for less toxic and more effective treatments for virus-associated
malignancies.
- Pomalidomide induces polyfunctional T cell, NK cell, and dendritic cell activation.
- Pomalidomide has shown promising activity in Kaposi sarcoma, likely due in part to
immune modulation.
- Downregulation and/or deregulation of immune surface markers by viruses can thwart
immunologic therapy, which may be prevented or reversed by pomalidomide.
- PD-L1 is expressed in virus-associated malignancies and modulation of PD-1 signaling is
a promising approach to treatment of virus-associated malignancies.
- Checkpoint inhibitors used alone have been shown to have some activity in certain
virus-induced tumors (e.g. Hodgkin and non-Hodgkin lymphomas, Merkel cell carcinoma, and
HPV-associated nasopharyngeal cancer). It is thus rational to explore combination
strategies that overcome viral-mediated immune evasion and provide potentially better
immunologic anti-tumor activity.
Objectives:
-Assess the safety and tolerability of pomalidomide plus nivolumab (Pom/Nivo) in participants
with virus-associated solid malignancies
Eligibility:
- Age greater than or equal to 18 years
- Histologically or cytologically proven selected virus-associated tumors that are
systemic, metastatic or locally advanced and not amenable to curative treatment options
or relapsed/refractory to first-line therapy
- For solid tumors or hematologic malignancies at least one measurable disease
- At least five measurable cutaneous KS lesions with no previous local radiation, surgical
or intralesional cytotoxic therapy to these measurable lesions.
- ECOG Performance Status (PS) less than or equal to 2
- Participants must be willing to give informed consent.
- Participants can be HIV positive or negative.
- Antiretroviral therapy (ART) for HIV+ patients
- Participants receiving other investigational agents will not be eligible.
Design:
- This is a Phase I study assessing the safety and efficacy of a fixed dose of nivolumab
combined with increasing doses of pomalidomide in participants with viral associated
malignancies.
- Up to 6 participants treated in a 3+3 dose de-escalation schema for pomalidomide using
one dose de-escalation and one dose escalation levels.
- Following identification of an optimal dose, an expansion phase will be initiated
through a protocol amendment. Up to 30 participants will be enrolled. Of these 12
participants must have a KS diagnosis and 12 participants must have EBV and/or
KSHV-associated lymphomas.
- Nivolumab will be administered IV at a dose of 480 mg at day one of each cycle, except
for cycle one when it will be administered on day 8. One cycle equals 28 days.
- Pomalidomide will be administered as an oral planned starting dose of 3 mg daily.
Pomalidomide will be given from day 1 to day 21 of each cycle.
- Participants will receive therapy up to 24 cycles or until unacceptable toxicity,
clinical progression, the participant s request to discontinue therapy, or PI decision.
- INCLUSION CRITERIA:
- Histologically or cytologically proven selected virus-associated tumors that are
systemic, metastatic or locally advanced and not amenable to curative treatment
options or are relapsed/refractory to first-line therapy as appropriate for each tumor
type as outlined below. Also, participants with eligible solid tumors, who after
evaluation by an expert in the area are deemed to be potentially curable after
extensive surgery, but refuse such surgical procedure due to associated disfigurement
and/or morbidity, may be eligible for the study with the necessary informed consent.
Pathology confirmation by NIH Department of Pathology is needed for eligibility. The
following tumor types listed below are eligible, and require assessing of virus
infection of the tumor cells with EBV EBER by in situ hybridization (ISH), KSHV LANA ,
p16, and Merkel cell polyomavirus large T antigen by immunohistochemistry (IHC) to
document the respective viral infection (EBV, KSHV, HPV, MCPvY) (116-119); or
detection of serum HBV surface antigen, anti-HBV core antibody, elevated HBV DNA viral
load, positive HVC antibody or elevated HCV RNA viral load. The tumor types studied in
the phase 1 trial will be as below. For tumors where >95% are known to be
virus-associated, such as cervical cancer, confirmation of virus status is not
required.
- EBV-positive Hodgkin lymphoma meeting the following criteria:
- Relapsed or refractory de novo classical Hodgkin lymphoma having failed
standard first-line therapy; and
- Unresponsive or progressive disease after treatment with brentuximab vedotin
or may be brentuximab vedotin na(SqrRoot) ve but is ineligible or unable to
receive brentuximab vedotin; and
- Unresponsive or progressive disease after checkpoint inhibitor therapy;
and
- Unresponsive or progressive disease after or is ineligible for autologous stem cell
transplant (auto-SCT)
--EBV-positive aggressive non-Hodgkin lymphomas (except primary CNS lymphoma and
Burkitt lymphoma) meeting the following criteria:
- Relapsed/refractory disease after standard first-line chemotherapy; and
- Relapsed disease after autologous stem cell transplant if indicated for histology (i.e
diffuse large B-cell lymphoma) or autologous stem cell transplant is not feasible; and
- Relapsed after CAR-T cell therapy for HIV-negative participants only if indicated for
histology (i.e diffuse large B-cell lymphoma) or CAR-T cell therapy is not feasible
- EBV-positive nasopharyngeal cancer unresponsive or progressive disease on or
after platinum-containing chemotherapy and/or radiotherapy
- EBV-positive gastric cancer that is unresponsive or progressive disease on or
after first-line chemotherapy
- EBV-positive leiomyosarcomas that is unresponsive or progressive disease on or
after 2 systemic regimens (CCRT/platinum-taxane)
- Kaposi sarcoma impairing physical wellbeing (for example, tumor edema, pain, skin
ulceration or breakdown, oral disease impairing function), no active KSHV-
associated multicentric Castleman disease in past 12 months, and one or more of
the following:
- Inadequate tumor response after 6 or more cycles of liposomal doxorubicin or
paclitaxel or other active cytotoxic agents (i.e. etoposide, bleomycin,
anthracyclines, vincristine, vinblastine); or
- Progressive disease while receiving liposomal doxorubicin or paclitaxel or other
active cytotoxic agents (i.e. etoposide, bleomycin, anthracyclines, vincristine,
vinblastine); or
- Intolerant of liposomal doxorubicin and paclitaxel
- Primary effusion lymphoma unresponsive or progressive disease on or after first-
line combination chemotherapy
- HPV-positive head and neck cancer that is unresponsive or progressive on or after
first-line combination chemotherapy +/- radiotherapy
- HPV-positive cervical cancer that is unresponsive or progressive on at least one
systemic regimen for recurrent (does not include initial CCRT) or metastatic
disease. Tumor HPV testing will not be a requirement for study eligibility for
cervical cancer.
- HPV-positive anal cancer that is unresponsive or progressive on or after
first-line combination chemotherapy +/- radiotherapy
- HPV-positive vaginal cancer that is unresponsive or progressive on or after
first- line chemotherapy
- HPV-positive penile cancer that is unresponsive or progressive on or after
surgery and first-line chemotherapy
- HPV-positive vulvar cancer that is unresponsive or progressive on or after first-
line combination chemotherapy
- MCPyV-positive Merkel cell carcinomas that is relapsed or refractory after prior
checkpoint inhibitor therapy
- HBV- or HCV-associated hepatocellular carcinoma that is not amenable to local
therapy or liver transplant and has progressed on first-line therapy with
sorafenib or levatinib or atezolizumab+bevacizumab
- For solid tumors, participants must have measurable disease, defined as at
least one lesion that can be accurately measured in at least one dimension
(longest diameter to be recorded for non-nodal lesions and short axis for
nodal lesions) as greater than or equal to 20 mm (greater than or equal to 2
cm) by chest x-ray or as greater than or equal to 10 mm (greater than or
equal to 1 cm) with CT scan, MRI, or calipers by clinical exam.
- For hematologic malignancies, participants must have measurable disease,
defined as at least one lesion that can be accurately measured in at least
one dimension (lymph nodes must measure greater than or equal to 15 mm in
the short axis and extranodal lesions must measure greater than or equal to
10 mm in the short axis with CT scan. For primary effusion lymphoma, body
cavity effusions may be followed as measurable disease by CT scan.
- For KS, participants must have measurable disease, defined as at least five
measurable cutaneous KS lesions with no previous local radiation, surgical
or intralesional cytotoxic therapy that would prevent response assessment
for that lesion.
- Prior immunomodulatory therapy and checkpoint inhibitor therapy is allowed
if previously tolerated without severe toxicities. Participants may not have
received chemotherapy, radiotherapy, monoclonal antibody therapy, or
targeted therapy within 2 weeks.
- Age greater than or equal to 18 years. Because no dosing or adverse event
data are currently available on the use of pomalidomide in combination with
nivolumab in participants <18 years of age, children are excluded from this
study.
- ECOG performance status less than or equal to 2 (Karnofsky greater than or
equal to 60%.
- Participants must have adequate organ and marrow function as defined below:
- leukocytes no lower limit
- absolute neutrophil count greater than or equal to 1,000/mcL
- platelets greater than or equal to 75,000/mcL
- total bilirubin less than or equal to institutional upper limit of normal
(ULN), except for participants with Gilbert disease or in whom the elevated
bilirubinemia is due to ART (must be grade less than or equal to 2)
- AST(SGOT)/ALT(SGPT) less than or equal to 3x institutional ULN
- glomerular filtration rate (GFR) >=30 mL/min/1.73 m2
-Participants with any HIV status are eligible; for HIV-positive participants:
- Must be on antiretroviral therapy (ART) > 4 weeks and with evidence of viral
suppression defined as HIV viral load < 400 copies/mL
- Must have no major (e.g. AIDS-defining) opportunistic infections within the last
6 months except for the following which will be allowed:
- Esophageal candidiasis treated within last 6 months or currently improving with
antifungal treatment
- Oral and/or genital HSV treated within last 6 months or currently improving with
antiviral treatment
- Mycobacterium avium infection in last 6 months or that has been treated for
at least 1 month
- For participants with evidence of chronic hepatitis B virus (HBV) infection,
participants must be on suppressive therapy.
- Participantatients with a history of hepatitis C virus (HCV) infection must
have been treated and cured. For participants with HCV infection who are
currently on treatment, they are eligible if they have an undetectable HCV
viral load.
- Able to take aspirin 81mg daily or a substitute thromboprophylaxis such as
low molecular weight heparin at a prophylactic dose.
- Participants with treated brain metastases are eligible if follow-up brain
imaging after central nervous system (CNS)-directed therapy shows no
evidence of progression.
- Participants with new or progressive brain metastases (active brain
metastases) or leptomeningeal disease are eligible if the treating physician
determines that immediate CNS specific treatment is not required and is
unlikely to be required during the first cycle of therapy.
- Participants with a prior or concurrent malignancy whose natural history or
treatment does not have the potential to interfere with the safety or
efficacy assessment of the investigational regimen are eligible for this
trial, such as carcinoma in situ or low-grade prostate carcinoma.
- Participants may not have cardiac or pulmonary abnormalities severe enough
that they would pose a danger to receive treatment. To mitigate risks for
cardiac AEs, screening EKG, echocardiogram, CPK, and troponin will be
required and significant abnormalities as determined by the PI will need to
be evaluated by Cardiology prior to enrollment. Participants with pulmonary
symptoms will be required to undergo pulmonary function testing and
Pulmonary evaluation at the discretion of the PI prior to enrollment.
- Current or history of systemic autoimmune disease requiring systemic
immunosuppressive therapy will not be allowed. Note: the following will not
be exclusionary: 1) the presence of laboratory evidence of autoimmune
disease (e.g. positive antinuclear antibody titer or lupus anticoagulant)
without associated symptoms; 2) clinical evidence of vitiligo or other forms
of depigmenting illness; 3) mild
autoimmunity not impacting the function of major organs (e.g. controlled Hashimoto
thyroiditis, limited psoriasis)
- Persons of childbearing potential (PCBP, defined as a sexually mature person assigned
female at birth who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or
2) has not been naturally postmenopausal for at least 24 consecutive months, i.e., has
had menses at any time in the preceding 24 consecutive months) must have a negative
serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL within 10-14
days prior to and again within 24 hours of starting pomalidomide and must either
commit to continued abstinence from receptive vaginal intercourse or begin TWO
acceptable methods of birth control, one highly effective method and one additional
effective method AT THE SAME TIME, at least 28 days before she starts taking
pomalidomide. PCBP must also agree to ongoing pregnancy testing. Persons assigned male
at birth must agree to use a latex condom during penetrative vaginal intercourse with
a PCBP even if they have had a vasectomy. All participants must be counseled at a
minimum of every 28 days about pregnancy precautions and risks of fetal exposure.
- Ability to understand and the willingness to sign a written informed consent document.
EXCLUSION CRITERIA:
- Participants who have had anticancer treatment within the last 2 weeks, unless the
cancer treatment is for a malignancy whose natural history or treatment does not have
the potential to interfere with the safety or efficacy assessment of the
investigational regimen are eligible for this trial, such as local treatment for
carcinoma in situ or hormonal therapy for prostate or breast carcinoma.
- Participants who have not recovered from adverse events due to prior anti-cancer
therapy (i.e., have residual toxicities > Grade 1) with the following exceptions:
- Elevated triglyceride attributed to ART and/or HIV (must be less than or equal to
Grade 2)
- Laboratory or clinical abnormalities that are assessed as more likely to be from
the underlying tumors, HIV disease, or other non-treatment causes will not be
considered an exclusion criterion.
- Alopecia, neuropathy and ototoxicity (i.e., AEs that are not expected to improve
within the washout period)
- Participants who are receiving any other investigational agents.
- Participants will be excluded if they are on systemic steroid therapy that cannot be
discontinued, with the exception of the use of prednisone or equivalent
<0.125mg/kg/day as replacement therapy. Inhaled or topical steroids are permitted.
- History of allergic reactions attributed to pomalidomide and/or nivolumab or compounds
of similar chemical or biologic composition to pomalidomide and/or nivolumab.
- Participants who have received prior allogeneic stem cell or organ transplant.
- Participants with severe uncontrolled intercurrent illness.
- Cirrhosis with Child-Pugh score of B or C
- Participants with psychiatric illness/social situations that would limit compliance
with study requirements.
- Pregnant and nursing persons are excluded from this study because pomalidomide is a
thalidomide analog. Thalidomide is a known human teratogen that causes severe birth
defects or embryo-fetal death. These potential risks may also apply to nivolumab based
on its mechanism of action and data from animal studies. In animal reproduction
studies, administration of nivolumab to cynomolgus monkeys from the onset of
organogenesis through delivery resulted in increased abortion and premature infant
death.
