M7824 in Subjects With HPV Associated Malignancies

Background:

- Early data from a small cohort of patients with HPV associated malignancies in a phase I
trial of M7824 has shown promising activity (NCT02517398). As of May 30, 2017, 4 of 9
patients (44%) with HPV associated malignancies have had preliminary evidence of
clinical benefit including:

- Patient with metastatic cervical cancer with a 25% reduction in her disease at 3 months

- Patient with metastatic P16+ head and neck cancer with an unconfirmed partial response
(PR) at 6 weeks

- Patient with metastatic anal cancer with a durable PR ongoing 9 months after starting
treatment

- Patient with metastatic cervical cancer with a durable complete response (CR) ongoing 15
months after starting treatment.

- Notably, the P16+ head and neck cancer patient with unconfirmed PR, anal cancer patient
with durable PR and cervical cancer patient with durable CR all have HPV+ disease.

- Metastatic or refractory/recurrent HPV associated malignancies (cervical, anal,
oropharyngeal cancers etc.) are often incurable and poorly palliated by standard
therapies.

- TGF R1 pathway signaling and overexpression are significantly associated with HPV+
cancers.

- PD-1 inhibitors have produced a 12-20% response rate for these diseases. M7824 is a
novel bifunctional fusion protein composed of monoclonal antibodies against human PD- L1

and soluble extracellular domain of human TGF- receptor II (TGF- RII), which functions as a
TGF- "trap."

- Immune related adverse events with M7824 in the phase I trial to date have been on par
with other PD-1/PD-L1 inhibitors, suggesting a manageable safety profile.

- EMD Serono has an ongoing expansion cohort evaluating M7824 in patients with HNSCC as
well as in cervical cancer excluding neuroendocrine cervical cancer.

Objective:

-To determine the objective response rate (ORR) according to the Response Evaluation Criteria
in Solid Tumors (RECIST 1.1) in subjects with recurrent or metastatic HPV associated
malignancies.

Eligibility:

- Age greater than or equal to 18 years old

- Subjects with cytologically or histologically confirmed locally advanced or metastatic
HPV

associated malignancies including:

- Non-Neuroendocrine Cervical cancers

- P16+ Oropharyngeal cancers

- Anal cancers

- Vulvar, vaginal, penile, squamous cell rectal and neuroendocrine cervical cancers

- Other locally advanced or metastatic solid tumors (e.g. lung, esophagus) that are known
HPV+

-Subjects must have measurable disease.

Design:

-This is a Phase II trial of M7824 in patients with recurrent or metastatic HPV associated

malignancies.

-Patients will be scheduled to receive 1,200 mg of M7824 IV every 2 weeks until off treatment

criteria are met.

-There will be six cohorts: (1) Patients with anal cancer whose disease is na"ve to
checkpoint

inhibition, (2) Patients with non-neuroendocrine cervical cancer na"ve to checkpoint
inhibition,

(3) Patients with P16+ oropharyngeal cancers na"ve to checkpoint inhibition, and (4) Patients
with other rare HPV associated tumors (e.g. squamous cell rectal, vulvar, vaginal, penile
cancer, neuroendocrine cervical) na"ve to checkpoint inhibition, (5) Patients with any HPV
associated cancers whose disease is refractory to checkpoint inhibition. Patients who are
determined to be HPV negative after enrolling will be taken off of their previously assigned
cohort and reassigned to cohort 6 and their slot on their previously assigned cohort will be
replaced.

-Cohorts 1-5 of the trial will be conducted using a Simon two-stage phase II trial design.

- INCLUSION CRITIERIA:

- Age greater than or equal to 18 years.

- Ability of subject to understand and the willingness to sign a written informed
consent document.

- Subjects with cytologically or histologically confirmed locally advanced or metastatic
HPV associated malignancies including:

- Non-Neuroendocrine Cervical cancers

- P16+ Oropharyngeal cancers

- Anal cancers

- Vulvar, vaginal, penile, squamous cell rectal and neuroendocrine cervical cancers

- Patients must have disease that is not amenable to potentially curative resection

- Subjects must have measurable disease

- ECOG performance status less than or equal to 2

- Adequate hematologic function at screening, as follows:

- Absolute neutrophil count (ANC) greater than or equal to 1 x 10^9/L

- Hemoglobin greater than or equal to 9 g/dL

- Platelets greater than or equal to 75,000/microliter.

- Adequate renal and hepatic function at screening, as follows:

- Serum creatinine less than or equal to 1.5 x upper limit of normal (ULN) OR
creatinine clearance (CrCl) greater than or equal to 40 mL/min according to the
Cockcroft-Gault formula: CrCl= ((140-age) x (weight in kg) x (0.85, if
female))/72 x Serum Creatinine (mg.dL)

- Bilirubin less than or equal to 1.5 x ULN OR in subjects with Gilbert's syndrome,
a total bilirubin less than or equal to 3.0 x ULN

- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) less than or
equal to 2.5 x ULN, unless liver metastases are present, then values must be less
than or equal to 3 x ULN)

- The effects of M7824 on the developing human fetus are unknown; thus, women of
childbearing potential and men must agree to use adequate contraception (hormonal or
barrier method of birth control; abstinence) prior to study entry, for the duration of
study participation and up to 120 days after the last dose of the drug. Should a woman
become pregnant or suspect she is pregnant while she or her partner is participating
in this study,she should inform her treating physician immediately.

- Patients serologically positive for HIV, Hep B, Hep C are eligible as long as the
viral loads are undetectable by quantitative PCR. HIV positive patients must have CD4
count greater than or equal to 300 cells oer cubic millimeter at enrollment, be on
stable antiretroviral therapy and have no reported opportunistic infections within 12
months prior to enrollment.

EXCLUSION CRITERIA:

-Pregnant women are excluded from this study because this drug has not been tested in
pregnant women and there is f 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 with M7824, breastfeeding should be discontinued if the mother is
treated with M7824.

- Patients with prior investigational drug, chemotherapy, immunotherapy or any prior
radiotherapy (except for palliative bone directed therapy) within the past 28 days
prior to the first drug administration except if the investigator has assessed that
all residual treatment-related toxicities have resolved or are minimal and feel the
patient is otherwise suitable for enrollment.

- Major surgery within 28 days prior to the first drug administration (minimally
invasive procedures such as diagnostic biopsies are permitted).

- Known intolerance to or life threatening side effects resulting from prior checkpoint
inhibitor therapy.

- Known active brain or central nervous system metastasis (less than 2 months out from
definitive radiotherapy or surgery), seizures requiring anticonvulsant treatment (<3
months) or clinically significant cerebrovascular accident (<3 months). In order to be
eligible patients must have repeat CNS imaging at least two months after definitive
treatment showing stable CNS disease. Patients with evidence of intratumoral or
peritumoral hemorrhage on baseline imaging are also excluded unless the hemorrhage is
grade less than or equal to 1 and has been shown to be stable on two consecutive
imaging scans.

- Active autoimmune disease that might deteriorate when receiving an immunostimulatory
agent with exception of:

- diabetes type I, eczema, vitiligo, alopecia, psoriasis, hypo- or hyperthyroid
disease or other mild autoimmune disorders not requiring immunosuppressive
treatment;

- Subjects requiring hormone replacement with corticosteroids are eligible if the
steroids are administered only for the purpose of hormonal replacement and at
doses less than or equal to 10 mg of prednisone or equivalent per day;

- Administration of steroids for other conditions through a route known to result
in a minimal systemic exposure (topical, intranasal, intro-ocular, or inhalation)
is acceptable;

- Subjects on systemic intravenous or oral corticosteroid therapy with the
exception of physiologic doses of corticosteroids (less than or equal to the
equivalent of prednisone 10 mg/day) or other immunosuppressives such as
azathioprine or cyclosporin A are excluded on the basis of potential immune
suppression. For these subjects these excluded treatments must be discontinued at
least 1 weeks prior to enrollment for recent short course use (less than or equal
to 14 days) or discontinued at least 4 weeks prior to enrollment for long term
use (>14 days). In addition, the use of corticosteroids as premedication for
contrastenhanced studies is allowed prior to enrollment and on study.

- Subjects with a history of serious intercurrent chronic or acute illness, such as
cardiac or pulmonary disease, hepatic disease, or other illness considered by the
Investigator as high risk for investigational drug treatment.

- History of second malignancy within 3 years of enrollment except for the following:
adequately treated non-melanoma skin cancer, cervical carcinoma in situ, superficial
bladder cancer or other localized malignancy which has been adequately treated.

- Known severe hypersensitivity reactions to monoclonal antibodies (Grade greater than
or equal to 3 NCI CTCAE v4.03)

- Receipt of any organ transplantation requiring ongoing immunosuppression.

- Patients with vulvar cancer originating from differentiated vulvar intraepithelial
neoplasia (d-VIN), as opposed to vulvar intraepithelial neoplasia of usual type, are
excluded. Vulvar squamous cell carcinoma originating from differentiated VIN (d-VIN)
is HPV negative; however, rare cases of HPV positive d-VIN can occur. Patients are not
excluded if their tumor has tested positive for HPV or there is no documentation of
prior VIN type.