On August 17, 2018 Tolero Pharmaceuticals, Inc., a clinical-stage biopharmaceutical company focused on developing treatments for hematologic and oncologic diseases, reported that it has entered into a clinical research collaboration with AbbVie, a research-based global biopharmaceutical company, exploring the potential of combination therapy with AbbVie’s venetoclax and Tolero’s investigational agent, alvocidib, for the treatment of relapsed/refractory acute myeloid leukemia (AML) (Press release, Tolero Pharmaceuticals, AUG 17, 2018, View Source [SID1234528982]).

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Alvocidib is a small molecule inhibitor of cyclin-dependent kinase 9 (CDK9), which controls the expression of a survival factor, MCL-1. Venetoclax is a small molecule inhibitor of B-cell lymphoma-2 (BCL-2). Both MCL-1 and BCL-2 are key proteins used by certain cancer cells to avoid apoptosis, and non-clinical studies have shown that cancer cells can resist inhibition of BCL-2 by using MCL-1 to avoid cell death. Alvocidib is currently in Phase II development for the treatment of MCL-1-dependent AML.

"We are very pleased to announce our clinical research collaboration with AbbVie, as it marks an important step in the development of this novel agent for patients with relapsed/refractory AML," said David J. Bearss, Ph.D., Chief Executive Officer of Tolero. "Preclinical data suggest that the mechanisms of action for venetoclax and alvocidib may synergistically drive apoptosis in cancer cells. We hope to further investigate this hypothesis with our planned trial of this combination therapy in patients with relapsed/refractory AML."

"This is a unique opportunity to bring together and investigate two first and only in class compounds to help patients with AML," said Neil Gallagher M.D., Ph.D, Vice President, Head of Global Oncology Development, AbbVie. "There is an urgent need for new therapies, particularly in patients who either did not respond well to initial therapy or who subsequently relapsed. AML is a complex disease at the cellular level. Therefore, combining alvocidib with venetoclax, which have distinct but potentially complementary mechanisms for targeting the leukemia cells, makes a lot of sense from a scientific perspective."

Under the terms of the agreement, Tolero and AbbVie will equally share all development expenses. Tolero will retain full commercial rights for alvocidib and AbbVie will retain full commercial rights for venetoclax.

About Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is a rapidly progressing cancer that is most common in the elderly.1 The disease forms in the bone marrow and impairs the normal function of the bone marrow to make healthy blood cells. Following an intensive regimen of chemotherapy treatment, a large portion of patients experience a relapse or have residual (or refractory) leukemic cells in their marrow. Patients with AML have a poor prognosis and those with relapsed or refractory disease currently have limited treatment options.

About Venetoclax

VENETOCLAX is an oral B-cell lymphoma-2 (BCL-2) inhibitor that targets a specific protein in the body called BCL-2.2 When you have CLL, BCL-2 may build up and prevent cancer cells from self-destructing naturally.2 VENCLEXTA/VENCLYXTO targets BCL-2 in order to help restore the process of apoptosis.2 Through apoptosis, your body allows cancer cells and normal cells to self-destruct.2

VENETOCLAX is being developed by AbbVie and Roche. It is jointly commercialized by AbbVie and Genentech, a member of the Roche Group, in the U.S. and by AbbVie outside of the U.S. Together, the companies are committed to BCL-2 research with venetoclax, which is currently being evaluated in clinical trials in several hematologic cancers.

VENETOCLAX is currently approved in more than 50 nations, including the U.S., and in the EU. AbbVie, in collaboration with Roche and Genentech, is currently working with regulatory agencies around the world to bring this medicine to eligible patients in need.

Use and Important Safety Information

Use

What is VENCLEXTA (venetoclax tablets)?

VENCLEXTA is a prescription medicine used to treat people with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), with or without 17p deletion, who have received at least one prior treatment.

It is not known if VENCLEXTA is safe and effective in children.

Important Safety Information

What is the most important information I should know about VENCLEXTA?

VENCLEXTA can cause serious side effects, including:

Tumor lysis syndrome (TLS). TLS is caused by the fast breakdown of cancer cells. TLS can cause kidney failure, the need for dialysis treatment, and may lead to death. Your healthcare provider will do tests for TLS. It is important to keep your appointments for blood tests. You will receive other medicines before starting and during treatment with VENCLEXTA to help reduce your risk of TLS. You may also need to receive intravenous (IV) fluids into your vein. Tell your healthcare provider right away if you have any symptoms of TLS during treatment with VENCLEXTA, including fever, chills, nausea, vomiting, confusion, shortness of breath, seizures, irregular heartbeat, dark or cloudy urine, unusual tiredness, or muscle or joint pain.

Drink plenty of water when taking VENCLEXTA to help reduce your risk of getting TLS. Drink 6 to 8 glasses (about 56 ounces total) of water each day, starting 2 days before your first dose, on the day of your first dose of VENCLEXTA, and each time your dose is increased.

Who should not take VENCLEXTA?

Certain medicines must not be taken when you first start taking VENCLEXTA and while your dose is being slowly increased because of the risk of increased tumor lysis syndrome.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. VENCLEXTA and other medicines may affect each other, causing serious side effects.
Do not start new medicines during treatment with VENCLEXTA without first talking with your healthcare provider.
Before taking VENCLEXTA, tell your healthcare provider about all of your medical conditions, including if you:

Have kidney or liver problems.
Have problems with your body salts or electrolytes, such as potassium, phosphorus, or calcium.
Have a history of high uric acid levels in your blood or gout.
Are scheduled to receive a vaccine. You should not receive a "live vaccine" before, during, or after treatment with VENCLEXTA until your healthcare provider tells you it is okay. If you are not sure about the type of immunization or vaccine, ask your healthcare provider. These vaccines may not be safe or may not work as well during treatment with VENCLEXTA.
Are pregnant or plan to become pregnant. VENCLEXTA may harm your unborn baby. If you are able to become pregnant, your healthcare provider should do a pregnancy test before you start treatment with VENCLEXTA, and you should use effective birth control during treatment and for 30 days after the last dose of VENCLEXTA.
Are breastfeeding or plan to breastfeed. It is not known if VENCLEXTA passes into your breast milk. Do not breastfeed during treatment with VENCLEXTA.
What should I avoid while taking VENCLEXTA?

You should not drink grapefruit juice or eat grapefruit, Seville oranges (often used in marmalades), or starfruit while you are taking VENCLEXTA. These products may increase the amount of VENCLEXTA in your blood.

What are the possible side effects of VENCLEXTA?

VENCLEXTA can cause serious side effects, including:

Low white blood cell count (neutropenia). Low white blood cell counts are common with VENCLEXTA, but can also be severe. Your healthcare provider will do blood tests to check your blood counts during treatment with VENCLEXTA. Tell your healthcare provider right away if you have a fever or any signs of an infection.
The most common side effects of VENCLEXTA when used in combination with rituximab include low white blood cell count, diarrhea, upper respiratory tract infection, cough, tiredness, and nausea.

The most common side effects of VENCLEXTA when used alone include low white blood cell count, diarrhea, nausea, upper respiratory tract infection, low red blood cell count, tiredness, low platelet count, muscle and joint pain, swelling of your arms, legs, hands, and feet, and cough.

VENCLEXTA may cause fertility problems in males. This may affect your ability to father a child. Talk to your healthcare provider if you have concerns about fertility.

These are not all the possible side effects of VENCLEXTA. Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

About Alvocidib

Alvocidib is an investigational small molecule inhibitor of cyclin-dependent kinase 9 (CDK9) currently being evaluated in Zella 201, a Phase II study in patients with relapsed or refractory MCL-1 dependent acute myeloid leukemia, AML, in combination with cytarabine and mitoxantrone (NCT02520011). Alvocidib is also being evaluated in Zella 101, a Phase I clinical study evaluating the maximum tolerated dose, safety and clinical activity of alvocidib in combination with (7+3) in newly diagnosed patients with AML (NCT03298984).

About CDK9 Inhibition and MCL-1

MCL-1 is a member of the apoptosis-regulating BCL-2 family of proteins.3 In normal function, it is essential for early embryonic development and for the survival of multiple cell lineages, including lymphocytes and hematopoietic stem cells.4 In MCL-1–dependent AML, MCL-1 inhibits apoptosis and sustains the survival of leukemic blasts, which may lead to relapse or resistance to treatment.3,5 The expression of MCL-1 in leukemic blasts is regulated by cyclin-dependent kinase 9 (CDK9).6,7 Because of the short half-life of MCL-1 (2-4 hours), the effects of targeting upstream pathways are expected to reduce MCL-1 levels rapidly.6 Inhibition of CDK9 has been shown to block MCL-1 transcription, resulting in the rapid downregulation of MCL-1 protein, thus restoring the normal apoptotic regulation.3

On August 17, 2018 Bristol-Myers Squibb Company (NYSE:BMY) reported that Opdivo (nivolumab) received approval from the U.S. Food and Drug Administration (FDA) as the first and only Immuno-Oncology treatment option for patients with metastatic small cell lung cancer (SCLC) whose cancer has progressed after platinum-based chemotherapy and at least one other line of therapy (Press release, Bristol-Myers Squibb, AUG 17, 2018, View Source [SID1234528964]).1 Approval for this indication has been granted under accelerated approval based on overall response rate (ORR) and duration of response (DOR). Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.1

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"At Bristol-Myers Squibb, we recognize the critical need to provide patients with cancer therapies that may offer more durable responses – particularly for those living with hard-to-treat, aggressive diseases like small cell lung cancer,"2 said Sabine Maier, M.D., development lead, thoracic cancers, Bristol-Myers Squibb. "This approval builds on our heritage of bringing Immuno-Oncology therapies to patients with other types of thoracic cancers. It also reinforces our commitment to bringing transformative treatments to patients in urgent need of effective new options."

Opdivo is associated with the following Warnings and Precautions: immune-mediated pneumonitis, colitis, hepatitis, endocrinopathies, nephritis and renal dysfunction, skin adverse reactions, encephalitis, other adverse reactions; infusion reactions; and embryo-fetal toxicity.1 Please see the Important Safety Information section below.

This approval for Opdivo in patients with SCLC whose cancer has progressed after two or more prior lines of therapy was granted priority review from the FDA.

The approval was based on data from the SCLC cohort of the ongoing Phase 1/2 CheckMate -032 study evaluating Opdivo in patients who experienced disease progression after platinum-based chemotherapy.1 Of 109 patients receiving Opdivo after platinum-based chemotherapy and at least one other prior line of therapy, 12% (n=13/109; 95% CI: 6.5-19.5) responded to treatment based on assessment by a Blinded Independent Central Review (BICR), regardless of PD-L1 expression.1,3 Twelve patients had a partial response (11%), and one patient had a complete response (0.9%).1,3 Among these responders, the median DOR was 17.9 months (95% CI: 7.9-42.1; range: 3.0-42.1 months).3 Opdivo was discontinued in 10% of patients, and one dose was withheld in 25% of patients for an adverse reaction.1 Serious adverse reactions occurred in 45% of patients.1 The approved dosing for Opdivo in this indication is 240 milligrams administered every 2 weeks by intravenous infusion until disease progression or unacceptable toxicity.1

"While Immuno-Oncology innovations have dramatically changed how oncologists approach certain cancers, we have had limited progress for patients with small cell lung cancer," said Leora Horn, M.D., M.Sc., associate professor of medicine, Ingram associate professor of cancer research, director of the thoracic oncology program and assistant vice chairman for faculty development, Vanderbilt University Medical Center. "Today’s approval of nivolumab is particularly exciting considering it is the first checkpoint inhibitor approved for these specific patients, and now we can finally treat this devastating disease from a different angle."1

Small cell lung cancer is one of two main types of lung cancer and accounts for about 10% to 15% of all lung cancers.4 Small cell lung cancer is an aggressive disease, and symptoms often are not detected until the cancer is at an advanced stage.2 In the United States, about 27,000 cases of SCLC are expected to be diagnosed in 2018.5 From the time of diagnosis, five-year survival rates for extensive stage SCLC, or Stage IV, are about 2%.6

"Small cell lung cancer can be a very challenging disease, particularly for those who have already been through multiple types of treatment, as most patients relapse within a year of diagnosis,"7 said Andrea Ferris, president and chairman of LUNGevity Foundation. "This approval marks a major milestone for the patients touched by this unrelenting disease and may motivate them to pursue further treatment where there previously were no other approved options."

Approval Based on CheckMate -032 Trial

CheckMate -032 is a Phase 1/2 multicenter, multi-cohort, open-label and ongoing trial, including 245 patients with SCLC who had experienced disease progression after platinum-based chemotherapy treated with Opdivo monotherapy.1,8 Efficacy was based on 109 patients who had experienced disease progression after platinum-based chemotherapy and at least one other prior line of therapy.1 These patients received 3 mg/kg of Opdivo given by intravenous infusion over 60 minutes every 2 weeks and were included regardless of their PD-L1 status.1 Infusions were administered to patients until disease progression or unacceptable toxicity. The trial excluded patients with autoimmune disease, medical conditions requiring systemic immunosuppression, symptomatic interstitial lung disease, or untreated brain metastasis.1 Patients with treated brain metastases were eligible if neurologically stable.1

The first tumor assessments were conducted 6 weeks after the first dose and continued every 6 weeks for the first 24 weeks and every 12 weeks thereafter.1 The major efficacy outcome measures were confirmed ORR, which was further characterized by DOR, as assessed by a BICR.1 The median duration of therapy in patients treated with Opdivo in the CheckMate -032 trial was 1 month (range: 0 to 44.2+ months).1 Seventeen percent of patients received Opdivo for greater than 6 months, and 9% of patients received Opdivo for greater than one year.1

Select Safety Profile for the CheckMate -032 Trial

The safety was evaluated in 245 patients with SCLC who experienced disease progression after platinum-based chemotherapy.1 The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia, dyspnea, pneumonitis, pleural effusion and dehydration.1 The most common adverse reactions (reported in at least 20% of patients) were fatigue (45%), decreased appetite (27%), musculoskeletal pain (25%), dyspnea (22%), nausea (22%), diarrhea (21%), constipation (20%) and cough (20%).1,9

INDICATIONS

OPDIVO (nivolumab) is indicated for the treatment of patients with metastatic small cell lung cancer (SCLC) with progression after platinum-based chemotherapy and at least one other line of therapy. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

OPDIVO (nivolumab) is indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving OPDIVO.

OPDIVO (nivolumab) is indicated for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) with disease progression on or after platinum-based therapy.

IMPORTANT SAFETY INFORMATION

Immune-Mediated Pneumonitis

OPDIVO can cause immune-mediated pneumonitis. Fatal cases have been reported. Monitor patients for signs with radiographic imaging and for symptoms of pneumonitis. Administer corticosteroids for Grade 2 or more severe pneumonitis. Permanently discontinue for Grade 3 or 4 and withhold until resolution for Grade 2. In patients receiving OPDIVO monotherapy, fatal cases of immune-mediated pneumonitis have occurred. Immune-mediated pneumonitis occurred in 3.1% (61/1994) of patients.

Immune-Mediated Colitis

OPDIVO can cause immune-mediated colitis. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 (of more than 5 days duration), 3, or 4 colitis. Withhold OPDIVO monotherapy for Grade 2 or 3 and permanently discontinue for Grade 4 or recurrent colitis upon re-initiation of OPDIVO. In patients receiving OPDIVO monotherapy, immune-mediated colitis occurred in 2.9% (58/1994) of patients.

Immune-Mediated Hepatitis

OPDIVO can cause immune-mediated hepatitis. Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater transaminase elevations. Withhold OPDIVO for Grade 2 and permanently discontinue OPDIVO for Grade 3 or 4. In patients receiving OPDIVO monotherapy, immune-mediated hepatitis occurred in 1.8% (35/1994) of patients.

Immune-Mediated Endocrinopathies

OPDIVO can cause immune-mediated hypophysitis, immune-mediated adrenal insufficiency, autoimmune thyroid disorders, and Type 1 diabetes mellitus. Monitor patients for signs and symptoms of hypophysitis, signs and symptoms of adrenal insufficiency, thyroid function prior to and periodically during treatment, and hyperglycemia. Administer hormone replacement as clinically indicated and corticosteroids for Grade 2 or greater hypophysitis. Withhold for Grade 2 or 3 and permanently discontinue for Grade 4 hypophysitis. Administer corticosteroids for Grade 3 or 4 adrenal insufficiency. Withhold for Grade 2 and permanently discontinue for Grade 3 or 4 adrenal insufficiency. Administer hormone-replacement therapy for hypothyroidism. Initiate medical management for control of hyperthyroidism. Withhold OPDIVO for Grade 3 and permanently discontinue for Grade 4 hyperglycemia.

In patients receiving OPDIVO monotherapy, hypophysitis occurred in 0.6% (12/1994) of patients. In patients receiving OPDIVO monotherapy, adrenal insufficiency occurred in 1% (20/1994) of patients. In patients receiving OPDIVO monotherapy, hypothyroidism or thyroiditis resulting in hypothyroidism occurred in 9% (171/1994) of patients. Hyperthyroidism occurred in 2.7% (54/1994) of patients receiving OPDIVO monotherapy. In patients receiving OPDIVO monotherapy, diabetes occurred in 0.9% (17/1994) of patients.

Immune-Mediated Nephritis and Renal Dysfunction

OPDIVO can cause immune-mediated nephritis. Monitor patients for elevated serum creatinine prior to and periodically during treatment. Administer corticosteroids for Grades 2-4 increased serum creatinine. Withhold OPDIVO for Grade 2 or 3 and permanently discontinue for Grade 4 increased serum creatinine. In patients receiving OPDIVO monotherapy, immune-mediated nephritis and renal dysfunction occurred in 1.2% (23/1994) of patients.

Immune-Mediated Skin Adverse Reactions

OPDIVO can cause immune-mediated rash, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), some cases with fatal outcome. Administer corticosteroids for Grade 3 or 4 rash. Withhold for Grade 3 and permanently discontinue for Grade 4 rash. For symptoms or signs of SJS or TEN, withhold OPDIVO and refer the patient for specialized care for assessment and treatment; if confirmed, permanently discontinue. In patients receiving OPDIVO monotherapy, immune-mediated rash occurred in 9% (171/1994) of patients.

Immune-Mediated Encephalitis

OPDIVO can cause immune-mediated encephalitis. Evaluation of patients with neurologic symptoms may include, but not be limited to, consultation with a neurologist, brain MRI, and lumbar puncture. Withhold OPDIVO in patients with new-onset moderate to severe neurologic signs or symptoms and evaluate to rule out other causes. If other etiologies are ruled out, administer corticosteroids and permanently discontinue OPDIVO for immune-mediated encephalitis. In patients receiving OPDIVO monotherapy, encephalitis occurred in 0.2% (3/1994) of patients. Fatal limbic encephalitis occurred in one patient after 7.2 months of exposure despite discontinuation of OPDIVO and administration of corticosteroids.

Other Immune-Mediated Adverse Reactions

Based on the severity of the adverse reaction, permanently discontinue or withhold OPDIVO, administer high-dose corticosteroids, and, if appropriate, initiate hormone-replacement therapy. Across clinical trials of OPDIVO, the following clinically significant immune-mediated adverse reactions, some with fatal outcome, occurred in <1.0% of patients receiving OPDIVO: myocarditis, rhabdomyolysis, myositis, uveitis, iritis, pancreatitis, facial and abducens nerve paresis, demyelination, polymyalgia rheumatica, autoimmune neuropathy, Guillain-Barré syndrome, hypopituitarism, systemic inflammatory response syndrome, gastritis, duodenitis, sarcoidosis, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), motor dysfunction, vasculitis, aplastic anemia, pericarditis, and myasthenic syndrome.

If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, which has been observed in patients receiving OPDIVO and may require treatment with systemic steroids to reduce the risk of permanent vision loss.

Infusion Reactions

OPDIVO can cause severe infusion reactions, which have been reported in <1.0% of patients in clinical trials. Discontinue OPDIVO in patients with Grade 3 or 4 infusion reactions. Interrupt or slow the rate of infusion in patients with Grade 1 or 2. In patients receiving OPDIVO monotherapy as a 60-minute infusion, infusion-related reactions occurred in 6.4% (127/1994) of patients. In a separate study in which patients received OPDIVO monotherapy as a 60-minute infusion or a 30-minute infusion, infusion-related reactions occurred in 2.2% (8/368) and 2.7% (10/369) of patients, respectively. Additionally, 0.5% (2/368) and 1.4% (5/369) of patients, respectively, experienced adverse reactions within 48 hours of infusion that led to dose delay, permanent discontinuation or withholding of OPDIVO.

Embryo-Fetal Toxicity

Based on its mechanism of action, OPDIVO can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with an OPDIVO-containing regimen and for at least 5 months after the last dose of OPDIVO.

Lactation

It is not known whether OPDIVO is present in human milk. Because many drugs, including antibodies, are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from an OPDIVO-containing regimen, advise women to discontinue breastfeeding during treatment.

Serious Adverse Reactions

In Checkmate -032, serious adverse reactions occurred in 45% of patients receiving OPDIVO (n=245). The most frequent serious adverse reactions reported in at least 2% of patients receiving OPDIVO were pneumonia, dyspnea, pneumonitis, pleural effusion, and dehydration. In Checkmate 017 and 057, serious adverse reactions occurred in 46% of patients receiving OPDIVO (n=418). The most frequent serious adverse reactions reported in ≥2% of patients receiving OPDIVO were pneumonia, pulmonary embolism, dyspnea, pyrexia, pleural effusion, pneumonitis, and respiratory failure. In Checkmate 141, serious adverse reactions occurred in 49% of patients receiving OPDIVO (n=236). The most frequent serious adverse reactions reported in ≥2% of patients receiving OPDIVO were pneumonia, dyspnea, respiratory failure, respiratory tract infection, and sepsis.

Common Adverse Reactions

In Checkmate -032, the most common adverse reactions (≥20%) in patients receiving OPDIVO (n=245) were fatigue (45%), decreased appetite (27%), musculoskeletal pain (25%), dyspnea (22%), nausea (22%), diarrhea (21%), constipation (20%), and cough (20%). In Checkmate 017 and 057, the most common adverse reactions (≥20%) in patients receiving OPDIVO (n=418) were fatigue, musculoskeletal pain, cough, dyspnea, and decreased appetite. In Checkmate 141, the most common adverse reactions (≥10%) in patients receiving OPDIVO (n=236) were cough and dyspnea at a higher incidence than investigator’s choice.

On August 17, 2018 Mateon Therapeutics, Inc. (OTCQB:MATN), a biopharmaceutical company developing investigational drugs for the treatment of orphan oncology indications, reported that the U.S. Food and Drug Administration (FDA) placed a partial clinical hold on Study OX1222 during a telephone conversation held with the Company on August 16, 2018 (Press release, Mateon Therapeutics, AUG 17, 2018, View Source [SID1234528963]). OX1222 is the Company’s clinical trial of OXi4503 in combination with cytarabine for the treatment of relapsed/refractory acute myeloid leukemia and myelodysplastic syndromes. The partial clinical hold applies to the 12.2 mg/m2 dose of OXi4503. The FDA is allowing the study to continue to treat and enroll patients using a dose of 9.76 mg/m2 of OXi4503, which the Company previously tested in cohort 5 of Study OX1222.

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The partial clinical hold follows two potential dose-limiting toxicities (DLTs) observed at the 12.2 mg/m2 dose level that was being evaluated in cohort 6 of Study OX1222. These DLTs consist of one patient experiencing hypotension shortly following initial treatment with OXi4503, and another patient experiencing acute hypoxic respiratory failure approximately two weeks after receiving OXi4503 and cytarabine. Both events were deemed "possibly-related" to OXi4503, and both patients recovered following treatment. The protocol for Study OX1222 generally defines a DLT as any grade 3 serious adverse event (SAE) where a relationship to OXi4503 cannot be ruled out. The FDA has indicated that additional data on patients receiving 9.76 mg/m2 of OXi4503 must be evaluated before the Company resumes dosing at 12.2 mg/m2.

"Although it is disappointing that we are not currently continuing with the higher dose of OXi4503, we look forward to gathering more safety and efficacy data at the previous dose level, where we observed two complete remissions in the four patients that we treated," said William D. Schwieterman, M.D., Chief Executive Officer of Mateon.

On August 17, 2018 Endocyte, Inc. (Nasdaq:ECYT), a biopharmaceutical company developing targeted therapeutics for personalized cancer treatment, reported that two posters will be presented by Endocyte scientists at the ACS National Meeting & Exposition being held in Boston, MA from Aug. 19 – 23, 2018 (Press release, Endocyte, AUG 17, 2018, View Source [SID1234528962]).

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Presentations are as follows:

Abstract # MEDI 425
Title: Pro-Pyrrolobenzodiazepine (pro-PBD) bioconjugates, part 3: Design and synthesis of pro-PBD conjugates containing a self-immolative substituted disulfide linkers
When: August 22, 2018, from 7:00 pm to 9:00 pm
Session ID: General Poster Session
Location: Galleria, Westin Boston Waterfront

Abstract # MEDI 426
Title: Pro-Pyrrolobenzodiazepine (pro-PBD) bioconjugates, part 4: Design of novel oxime-based pro-PBD conjugates that release active drug via intramolecular diazepine-ring-closure
When: August 22, 2018, from 7:00 pm to 9:00 pm.
Session ID: General Poster Session
Location: Galleria, Westin Boston Waterfront

Website Information

Endocyte routinely posts important information for investors on its website, www.endocyte.com, in the "Investors & News" section. Endocyte uses this website as a means of disclosing material information in compliance with its disclosure obligations under Regulation FD. Accordingly, investors should monitor the "Investors & News" section of Endocyte’s website, in addition to following its press releases, SEC filings, public conference calls, presentations and webcasts. The information contained on, or that may be accessed through, Endocyte’s website is not incorporated by reference into, and is not a part of, this document.

On August 16, 2018 Immatics, a leading company in the field of cancer immunotherapy, reported that it has initiated enrollment of patients into a phase I trial of IMA202, its second T-cell Receptor (TCR)-transduced adoptive cell therapy program. IMA202 is an investigational immunotherapy which uses Immatics’ proprietary ACTengine approach and is based on genetic engineering of the patient’s own T cells to express an exogenous TCR (Press release, Immatics Biotechnologies, AUG 16, 2018, View Source [SID1234569550]). The goal is to redirect and activate the T cells to treat solid tumors. The single-center clinical study is now open for enrollment at The University of Texas MD Anderson Cancer Center in Houston, Texas.

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The study (IMA202-101) will include approximately 12 patients with relapsed and/or refractory solid tumors, including but not limited to advanced non-small cell lung cancer and hepatocellular carcinoma, for which no standard of care therapy is available.

Immatics’ ACTengine approach engineers the patients’ own T lymphocytes (a type of white blood cell) to express a novel, exogenous T-cell receptor (TCR) which is targeted to a site on the tumor identified by Immatics’ proprietary XPRESIDENT target discovery platform. ACTengine combines several innovative features:

TCRs specifically recognizing the XPRESIDENT-identified target are selected via Immatics’ proprietary high-throughput TCR discovery platform from the natural, human T-cell repertoire. The TCR used in this trial has been selected for highest specificity from more than one hundred TCRs using Immatics’ XPRESIDENT-guided on- and off-target toxicity screening.
The novel TCR recognizes its target with optimal affinity for an adoptive cellular therapy (ACT) approach.
The TCR-transduced T cells are activated and multiplied outside the body before being infused into the patient.
Patients are eligible for ACTengine cell therapy if the target of interest is present on the patient’s tumor as demonstrated by biomarker profiling.
The primary objective of the study is to evaluate the safety and tolerability of the ACTengine approach, and specifically IMA202, in target-positive solid cancer patients. The secondary objectives include the evaluation of feasibility, the persistence of T cells in vivo, and the assessment of anti-tumor activity and biomarkers. The IMA202 phase I trial will be conducted by the Department of Thoracic Oncology, the Department of Gastrointestinal Medical Oncology and the Department of Investigational Cancer Therapeutics at MD Anderson Cancer Center in Houston, Texas.

Stephen L. Eck, M.D., Ph.D., Chief Medical Officer of Immatics US, commented: "Regulatory approval to start our second clinical study in our ACTengine-based cell therapy program is a significant step for Immatics. This study exemplifies Immatics’ XPRESIDENT target discovery capability and TCR discovery pipeline which are industry-leading cancer immunotherapy platforms. We are very excited to combine these capabilities in a trial led by the world-class investigators from MD Anderson Cancer Center in order to develop exciting new treatment options for cancer patients."