Development Platform

Camptotheca acuminata

Vivacitas' Development Platform is focused on advancing two promising compounds, representing second- and third-generation Camptothecin derivatives, to treat especially tenacious malignancies. Molecules of the Camptothecin class originate from a native Chinese deciduous tree, Camptotheca acuminata, and have a long-standing clinical history as chemotherapeutic agents in a number of different oncologic settings. Camptothecins exert their therapeutic effects via their inhibition of topoisomerase I, an enzyme that plays a critical role in cell division.

Camptothecins: active lactone form and inactive carboxylate form

Despite the fact that 2nd generation Camptothecin-based drugs show therapeutic effects in a variety of settings, their use can be accompanied by dose-limiting toxicities, problematic pharmacokinetics, stability, and potency properties.

Nevertheless, it is worth noting that two marketed, second generation, off-patent Camptothecin-related drugs Hycamtin® and Camptosar®, together pulled in 1.5 B USD in revenue for 2012, even with their known side effect profiles.

Rubitecan/Orathecin and AR-67 are in the late stages of development and are being vigorously pursued as each offers potential improvements over commercially available Camptothecins, as discussed below.

AR-67

Protocol Design Stage in Orphan Indication

The lead program to Rubitecan, AR-67, is a third generation Camptothecin derivative showing potential benefits in patients. This neoplasm of the cerebral hemispheres poses a serious therapeutic challenge because by the time it is diagnosed, the cancer is already fully established. As a result, the median survival rate for untreated GBM is very poor at 3 months, with less than 50% of patients surviving at 1 year and only 3-5% of patients surviving 3 or more years.

The market opportunity for an effective therapy in GBM is expected to double over the next 4 years, and will likely be driven by the introduction of new diagnostic platforms targeted at earlier detection and intervention.

Expected GBM Therapeutic Market Growth

AR-67, an intravenously administered compound, is a specially modified Camptothecin designed to solve three major challenges; First, AR-67's modification results in improved pharmacokinetic and stability profiles that enable systemic dosing and suitable exposure to the drug. Second, AR-67's modified lipophilicity characteristics correlate well with a 16-fold improvement in potency (relative to marketed Camptothecins) as observed in clinical studies, suggesting that the therapeutic index has been widened, and might potentially reduce the dose-limiting toxicities often observed with Camptothecins. Lastly, AR-67 has demonstrated encouraging clinical activity in Phase II studies in patients, which will be studied further in future clinical trials.

AR-67: Phase I Toxicity Results

Phase I Trial

Title: A Phase I Study of AR-67 in Adult Patients with Refractory or Metastatic Solid Malignancies

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Dose Range:

  • Dose range: 1.2-12.4 mg/m2/day
  • AR-67 administered once daily for 5 days of an every 21 day

Patients/Methods:

  • 26 patients with varying refractory solid malignancies with metastatic or unresectable disease and/or standard curative or palliative measures no longer existed or were no longer effective
  • Patients had to be at least able to be ambulatory and carry out self-care and awake for 50% of waking hours.
  • No prior chemotherapy, molecularly targeted agents or radiation therapy was allowed within 2 weeks (6 weeks for mitomycin C or nitrosoureas), and no major surgery was allowed within 3 weeks
  • Prior Camptothecin therapy was allowed, but patients with allergic reactions attributed to compounds of similar chemical or biologic composition to AR-67 or subjects with prior grade 3 or 4 anaphylactic reaction to any product formulated with cremophor (i.e., paclitaxel) were excluded

Safety:

  • Maximum Tolerated Dose:5 mg/m2/day
  • Dose limiting toxicities: observed in 5/26 patients
    • 1 out of 26 subjects exhibited grade 4 febrile neutropenia
    • 1 out of 26 subjects exhibited grade 3 fatigue
    • 2 out of 26 subjects exhibited grade 4 thrombocytopenia
  • All Dose limiting toxicities resolved without permanent sequellae
  • Common Grade 3 and 4 toxicities included: leukocytopenia (23%), thrombocytopenia (15.4%), fatigue (15.4%), neutropenia (11.5%), and anemia (11.5%)
  • No patients with infusion related allergic reactions or diarrhea.

Efficacy:

  • Response rate was evaluable in 22 subjects
  • 1 subject with squamous cell carcinoma of the lung prolonged partial response at dosage level 5.5, received ten cycles of therapy
  • 4 subjects had stable disease
    • 1 patient at dosage level 7 with duodenal cancer (82 days)
    • 2 patients at dosage levels 5.5
  • 6 with small cell lung cancer (refractory disease, 91 days; sensitive relapse, 112 days)
  • 1 patient with non-small cell lung cancer at dose level 5.5 (74 days).

Conclusion:

  • While fatigue and hematologic toxicities are hallmarks of Camptothecins, the lack of diarrhea seen in the present trial is notable compared to other drugs of this class, particularly irinotecan.
  • AR-67 is well tolerated
  • At the maximum tolerated dosage, toxicities were manageable and no diarrhea or hypersensitivity reactions were seen.
  • Interestingly, a confirmed partial response was noted in a patient with non-small cell lung cancer, who remained on therapy for ten cycles.
  • Further clinical testing of AR-67 is warranted and ongoing.

REF: Arnold SM, Rinehart JJ, Tsakalozou E, Eckardt JR, Fields SZ, Shelton BJ, DeSimone PA, Kee BK, Moscow JA, Leggas M. A phase I study of 7-t-butyldimethylsilyl-10-hydroxycamptothecin in adult patients with refractory or metastatic solid malignancies. Clin Cancer Res. 2010 Jan 15;16(2):673-80. PMID:20068096

AR-67: Encouraging Clinical Phase II Results

Phase II Trial

Title:  A Phase 2 Study of AR-67 in Adult Patients

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Study Design: Open label, Multicenter, Multinational Clinical Study, US and Canada

Patients/Methods:

  • 58 patients planned
  • 46 total enrolled due to early termination:
    • Cohort 1: 31 patients in the non-recent (>90 days) bevacizumab failure cohort
    • Cohort 2: 13 patients in the bevacizumab failure cohort
    • 2 additional patients without reported bevacizumab history.
  • 45/46 patients: received at least one dose of AR-67 and were analyzed for safety
  • Grade IV GBM or gliosarcoma at primary diagnosis or recurrence with a life expectancy of ≥ 2 months and able to care for most of his/her personal and needs only occasional assistance

End Points:

6 patients/32 achieved 6-month Progression Free Survival

Overall Response Rate = 10%, 3/31
Overall Disease Control Rate = 17%, 8/46

Cohort1 (bevacizumab naïve):
3/31/46 patients partial response
      (1 patient durable partial response)
5/31/46 Stable disease

Safety:

  • 4 deaths in this study; one death occurred during screening and prior to study drug administration, and 3 occurred following drug administration that were due to disease progression.
  • In Cohort 1, the most common TEAEs were fatigue (27%), constipation (23%), headache (23%), anemia (23%), and thrombocytopenia (20%).
  • In Cohort 2, the most common TEAEs were nausea (31%), constipation (15%), diarrhea (15%), fatigue (15%), muscular weakness (15%), confusional state (15%), headache (15%), and hiccups (15%).
  • A total of 17 (38%) patients experienced at least 1 SAE, with the most common being headache (3 patients). Two (4%) patients experienced a TEAE, with an outcome of death (i.e., a fatal TEAE). For both patients, the Grade 5 TEAE was disease progression and was considered unrelated to the study drug.
  • 9 (20%) patients discontinued the study drug because of a TEAE, most commonly due to nervous system disorders, including headache (3 patients), ataxia, hemiparesis, and intracranial venous sinus thrombosis (1 patient each).

Conclusion:

  • AR-67 was well tolerated and exhibited a safety profile like other Camptothecins.
  • AR-67 had a favorable Progression Free Survival rate warranting further investigation, specifically as a second line chemotherapy and as salvage chemotherapy for bevacizumab naïve patients.

In the near term, Vivacitas is focused on designing a Phase III clinical trial while building on the benefits conferred by the recently issued Orphan Designation.

Rubitecan/Orathecin ("RUBI")

Targeted for Pancreatic Cancer, an Orphan Indication

Cancer of the pancreas is an extraordinarily difficult neoplasm to treat. While pancreatic cancer survival rates are improving from decade to decade, the disease is still considered incurable. According to the American Cancer Society, for all stages of pancreatic cancer combined, the five-year survival rate is 7%.

Through the efforts of Dr. Rubinfeld, Vivacitas acquired its Development Platform asset, Rubitecan, in late 2016. The company targeted this program because of three key elements suggesting an important role for this Camptothecin compound in the fight against pancreatic cancer:

  1. RUBI, a second-generation Camptothecin, is the only orally available formulation, potentially allowing more flexibility in dose and schedule of administration, particularly in relation to combination therapeutic regimens. Currently, drugs of this class are delivered intravenously.
  2. The program has garnered US FDA Orphan Drug Designation in two indications: pancreatic cancer and pediatric HIV/AIDS, as an anti-viral therapy, as well as Fast Track Designation in pancreatic cancer, thereby potentially offering attractive downstream advantages.
  3. Most importantly, RUBI has already demonstrated promising clinical results as a second line therapy in Phase II and Phase III studies in patients with pancreatic cancer, as summarized below:

RUBITECAN/ORATHECIN Displays Encouraging Results in Phase II Trials in Pancreatic Cancer Patients

Phase II Trials

1st Trial

Title: A study of Rubitecan in Patients with Advanced Pancreatic Cancer

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Study Design: Single Center clinical trial, USA, St. Joseph's Hospital, Houston, TX

Patients/Methods:

  • 60 evaluated, 107 enrolled initially enrolled
  • 57/107 chemonaive
  • 50/107 ≥ 1 prior chemotherapy
  • 33/107 Gemcitabine failures
  • 60% of patients with distant metastases
  • The 47 patients that were not included did not receive 2 courses of therapy mostly due to rapid progression of disease, voluntary withdrawal, and death due to other causes. But they are included in subgroup analysis.
  • Patients likely to survive >2 months
  • No stabilization period, allowing patients with more severe disease to be enrolled
  • Dose Schedule: 1-1.5 mg/m2/day each week for 5 days, 2 days rest 4 weeks of treatment with oral rubitecan

End Points:

  • Median survival was 6.5 months for the 107 total patients and 8.7 months for the 60 evaluable patients, with one patient surviving at 44+ months
  • Of the 60 evaluable patients:
    • 7%, n=19 were responders (median survival 18.6 months, 6.5-44.7)
    • 7%, n=19 were stable (medial survival 9.7 months)
    • 6%, n=22 were non-responders (median survival 6.8 months)
  • Subgroup Analysis:
    • Median survival chemonaive 57/107: 7.3 months (0.3-18.6+ months)
    • Median survival 33/107 Gemcitabine failures: 4.7 months, with 2 patients 17.8+ and 24.6+months

Safety:

  • Primary dose-limiting toxicities were myelosuppression and interstitial cystitis, no deaths.

Conclusion:

  • Rubitecan is safe and efficacious in the treatment of advanced pancreatic cancer
  • It also shows modest success as a second-line therapy in treating gemcitabine failures

REF: Stehlin JS, Giovanella BC, Natelson EA, De Ipolyi PD, Coil D, Davis B, Wolk D, Wallace P, Trojacek A.  A study of 9-nitrocamptothecin (RFS-2000) in patients with advanced pancreatic cancer. Int J Oncol. 1999 May;14(5):821-31. PMID: 10200331

Investigator’s Brochure Orathecin, version September 13, 2002

2nd Trial

Title: An Open-Label, Multi-center, Phase II Study of Rubitecan Capsules in Pancreatic Cancer Patients who Failed Previous Chemotherapy (other than Gemcitabine)

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Study Design: Multicenter Clinical Trial, USA

Patients/Methods:

  • 58 patients enrolled
  • Treatment failure or relapse after ≥ 1chemotherapy regimen other than gemcitabine alone
  • All patients requiring only occasional assistance and were all at least 3 weeks recovered from surgery, chemotherapy, radiation, or immunotherapy
  • Heavily pretreated: 98% refractory, 72% received 2-5 prior chemotherapies
  • Dose Schedule: 5 mg/m2/day each week for 5 days, 2 days rest 4 weeks of treatment with oral rubitecan

End Points:

  • Median progression free survival for all patients 59 days (95% CI, 53-65 days)
  • Median survival: 92 days (95% CI, 76-124 days)
  • Time to radiological progression was 63 days unadjusted, 113 days adjusted for next scheduled appointment
  • 43/58 patients with measurable disease:
    • 7/43 patient partial response
  • Objective verified response rate of 10%, stable disease rate of 23%

Safety:

  • Treatment well tolerated
  • Discontinuation of treatment in 18 patients due to disease progression
  • Nausea and vomiting common adverse events

Conclusion:

  • This multicenter study confirms previous studies demonstrating activity in refractory disease and achieving partial responses or disease stabilization in patients with advanced pancreatic cancer.
  • The overall risk benefit of treatment with Rubitecan is favorable in advanced pancreatic cancer

REF: Clinical Study Report Protocol 2000-01

RUBITECAN/ORATHECIN: Positive Phase III Results in Pancreatic Cancer Patients: 3 Trials

1st Trial

Title: A Randomized Phase III Study of Rubitecan vs. Best Choice in 409 Patients with Refractory Pancreatic Cancer Report from a North-American Multi-Center Study

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Study Design: Multicenter clinical trial in USA

Patients/Methods:

  • 198 patients randomized to rubitecan and 211 to Best Choice
  • >90%, n=368 were resistant to prior chemotherapy
  • 70%, n=286 were refractory to 2 or more prior regimens
  • 49%, n=103 of Best Choice patients crossed over to rescue therapy with rubitecan at time of failure
  • All patients had a life expectancy of at least 2 months, with all patients requiring only occasional assistance and were all at least 2 weeks recovered from surgery, chemotherapy, radiation, or immunotherapy

End Points:

  • No difference in median survival: 108 days in rubitecan and 94 days in best choice
  • Significant survival advantage seen for best choice patients crossed over to rubitecan: 147 days vs 60 days, p< 0.0001
  • Patients with measurable disease (59%, n= 117, ORA only patients, not including BC cross over patients) there were 12 independently verified responders for ORA for a response rate of 11%, versus to 1 responder BC, p<0.001
  • Stable disease was also more common on rubitecan: 44 patients vs. 27 patients
  • More than 2-fold more patients on rubitecan achieved tumor growth control: 28% vs. 13%
  • Median Progression Free Survival significantly longer for rubitecan: 58 days vs. 48 days, p =0.003

Safety:

  • Rubitecan was well tolerated with <5% discontinued treatment due to toxicity
  • Grade 3–4 toxicity was more common for rubitecan (neutropenia 28% vs. 14%; anemia 21% vs. 9%; nausea/vomiting 14% vs. 9%; diarrhea 12% vs. 5%).

Conclusion:

  • Rubitecan can achieve tumor growth control and significant progression free survival with an acceptable risk- benefit ratio.
  • These results suggest that rubitecan might address the urgent need of patients with advanced pancreatic cancer, who now have very limited options in treatment.

REF: Jacobs AD, et al. A randomized phase III study of rubitecan (ORA) vs. best choice (BC) in 409 patients with refractory pancreatic cancer report from a North-American multi-center study.J Clin Oncol. 2004 Jul 15;22 (14_suppl):4013.PMID:28016455

Clinical Study Report Protocol 2000-09

2nd Trial

Title: Randomized Study of Rubitecan versus 5-Fluorouracil (5-FU) in Pancreatic Cancer Patients that have Progressive Disease Following Gemcitabine Treatment

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Study Design: Multicenter, multinational clinical trial in USA, Europe, and Canada.

Patients/Methods:

  • 224 to oral rubitecan and 224 to IV 5-FU for the classical intent to treat analysis.
  • A total of 93 (41%) 5-FU patients crossed over to treatment with rubitecan.
  • All patients had a life expectancy of at least 2 months, with all patients requiring only occasional assistance

End Points:

  • There was no statistically significant difference in medial survival: 93 days rubitecan and 116 days 5-FU.
  • A significant survival difference was noted in an analysis per protocol therapy (censoring patients at time of crossover) 93 days rubitecan 66 days 5-FU (p=0.005)
  • Median survival (without censoring) was also different between crossover and non-crossover patients from the 5-FU arm (from randomized baseline), 147 days vs. 60 days.
  • No difference progression free survival: 56 days rubitecan and 56 days 5-FU.
  • Objective Clinical Response Rate: Tumor responses noted in 7 (2 complete response, 5 partial response) rubitecan patients vs. 1 (partial response) 5-FU patient. (6% for rubitecan vs 1% for 5 FU, p = 0.03)

Safety:

  • Half of all adverse events judged related to rubitecan and 5FU.
  • Hematologic and urogenital events were higher in rubitecan arm.
  • Hematuria (blood in the urine) was common at 14%, only 1% of the cases were severe.

Conclusion:

  • Rubitecan consistently is equivalent or superior to 5-FU.
  • More patients on rubitecan achieve objective tumor response.
  • The real benefit of rubitecan may be in its use in combination regimens.
  • Rubitecan, an oral agent, is a convenient alternative to 5-FU, an approved drug agent given IV, in the palliative treatment of advanced pancreatic cancer.

Ref: Clinical Study Report Protocol 2000-06

3rd Trial

Title: Phase III Randomized Study of Rubitecan versus Gemcitabine in Chemonaive Pancreatic Cancer Patients

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Study Design: Multicenter trial in USA and Canada

Patients/Methods:

  • 496 patients in Rubitecan arm and 498 in Gemcitabine arm
  • Chemonaive patients, with low dose 5-FU as a radiation sensitizer allowed
  • All patients were a minimum of 30 days past randomization of an investigational agent(s)
  • All patients required only occasional assistance and were all at least 2 weeks recovered from surgery and at least 3 weeks from radiation or immunotherapy

End Points: final analysis in process

Safety:

  • 50% of all adverse events were judged related to either rubitecan or gemcitabine
  • Gastrointestinal and urogenital events notably higher in rubitecan arm, but hematologic events were notably higher in gemcitabine patients.
  • Severe or life threating events with a higher incidence in the Rubitecan group included digestive events: abdominal pain (14% vs. 10%), diarrhea (12% vs. 4%), nausea (20% vs. 13%), and vomiting (17% vs. 10%).
  • Severe adverse events with a lower incidence in rubitecan include myelosupression: leukopenia (19% vs. 24%), thrombocytopenia (5% vs. 10%), dyspnea (4% vs. 9%), and pneumonia (2% vs. 6%).
  • Incidence of infections was generally similar in the two treatment groups.
  • Overall infection rate was 10% for rubitecan and 13% for gemcitabine treated patients. Sepsis in 5% in both groups.

Conclusion:

  • Safety Profile is comparable to and in some cases superior to gemcitabine with Gastrointestinal events more commonly reported with rubitecan and hematologic, respiratory, and skin events more commonly reported for gemcitabine.
  • We await our efficacy results that are currently in process.

Ref: Clinical Study Report Protocol 2000-02, Interim Safety Report 2000-02